Controlling magnetic nanoparticles to increase vascular flow

ABSTRACT

Some embodiments provide a system for external manipulation of magnetic nanoparticles in vasculature using a remotely placed magnetic field-generating stator. In one aspect, the systems and methods relate to the control of magnetic nanoparticles in a fluid medium using permanent magnet-based or electromagnetic field-generating stator sources. Such a system can be useful for increasing the diffusion of therapeutic agents in a fluid medium, such as a human circulatory system, which can result in substantial clearance of fluid obstructions, such as vascular occlusions, in a circulatory system resulting in increased blood flow.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/485,613 filed May 31, 2012, which is a continuation of U.S. patentapplication Ser. No. 13/471,908 filed May 15, 2012, which is acontinuation-in-part of U.S. patent application Ser. No. 13/505,447,filed May 1, 2012, which is a National Phase Application ofInternational Application Number PCT/US2010/055133, filed Nov. 2, 2010,published as International Publication Number WO 2011/053984 on May 5,2011, which claims the benefit of U.S. Provisional Application Ser. No.61/280,321 filed on Nov. 2, 2009. This application hereby expresslyincorporates by reference each of the above-identified applications intheir entirety.

FIELD

This disclosure relates to systems and methods for facilitatingintroduction and external manipulation of magnetic nanoparticles withina circulatory system.

DESCRIPTION OF THE RELATED ART

The treatment of fluid obstructions in the circulatory system, includingvascular occlusions in vessels of the brain and vessels of theextremities, has included the use of drugs that can dissolve theobstructions and obstruction removal devices, e.g., thrombectomydevices. However, side-effects of such drugs are difficult to controland such obstruction removal devices often involve invasive proceduresthat cause unintended or secondary tissue damage. Both the use of drugsat normal dosages and the use of invasive thrombectomy devices can causedeath.

SUMMARY

In several embodiments, a therapeutic system is provided comprising (a)a magnet having a magnetic field and a gradient for controlling magneticrotors in a circulatory system, and (b) a controller for positioning androtating the field and the gradient in a manner to agglomerate and movethe magnetic rotors with respect to a therapeutic target in thecirculatory system. Using the therapeutic system, contact of thetherapeutic target with a pharmaceutical composition in the circulatorysystem is increased according to one embodiment. In various aspects, thepharmaceutical composition can be attached to the magnetic rotor, and inother aspects can be administered to the circulatory system separatefrom the magnetic rotors. In certain instances, the pharmaceuticalcomposition can be a thrombolytic drug.

Therapeutic targets of the system can include fluid obstructions suchas, but not limited to, atherosclerotic plaques, fibrous caps, fattybuildup, coronary occlusions, arterial stenosis, arterial restenosis,vein thrombi, arterial thrombi, cerebral thrombi, embolism, hemorrhage,very small vessels, other fluid obstructions, or any combination ofthese. Therapeutic targets of the system can also include any organ ortissue (e.g., tumor) of the body. For example, therapeutic targets canbe targets identified for stem cell and/or gene therapy. In variousaspects, the circulatory system is vasculature of a patient, inparticular, a human patient.

In various embodiments, the therapeutic system comprises a permanentmagnet coupled to a motor, and the controller controls a motor toposition the magnet at an effective distance and an effective plane withrespect to the therapeutic target, and rotates the magnet at aneffective frequency with respect to the therapeutic target. In variousembodiments, the therapeutic system comprises an electromagnet having amagnetic field strength and magnetic field polarization driven byelectrical current, and the controller positions the electromagnet at aneffective distance and an effective plane with respect to thetherapeutic target, and rotates the magnetic field of the electromagnetby adjusting the electrical current.

The therapeutic system can further include a display for viewing themagnetic rotors and therapeutic target, and a user interface forcontrolling the magnetic rotors, such that a user can control themagnetic rotors to clear, remove, or reduce in size a therapeutic targetby adjusting a frequency of the rotating magnetic field, an orientationplane of the rotating magnetic field with respect to the therapeutictarget, and/or a distance of the rotating magnetic field with respect tothe therapeutic target. In various aspects, the therapeutic target canbe a thrombosis or clot in a human blood vessel. In various aspects, themagnetic rotors can be magnetic nanoparticles injected into thecirculatory system. The magnetic nanoparticles can be coated oruncoated.

In several embodiments, the magnetic rotors move through the fluid inthe circular motion by repeatedly (a) walking end over end along theblood vessel away from the magnetic field in response to the rotation ofthe rotors caused by torque exerted on the rotors by a rotating magneticfield and an attractive force (e.g., a directed gradient) of themagnetic field, and (b) flowing back through the fluid towards themagnetic field in response to the rotation of the rotors and theattractive force (e.g., directed gradient) of the magnetic field.

In some embodiments, a therapeutic system is provided for increasingfluid flow in a circulatory system comprising a magnet having a magneticfield for controlling a magnetic tool in the fluid, and a controllerconfigured to position and rotate the magnetic field with respect to thetherapeutic target to rotate an abrasive surface of the magnetic tooland maneuver the rotating abrasive surface to contact and increase fluidflow through or around the therapeutic target. In various aspects, thecirculatory system can be vasculature of a patient, particularly a humanpatient. In various aspects, the magnetic tool can be coupled to astabilizing rod, and the magnetic tool rotates about the stabilizing rodin response to the rotating magnetic field. In some aspects, themagnetic tool can include an abrasive cap affixed to a magnet whichengages and cuts through the therapeutic target. In certain aspects, thecontroller positions the magnetic tool at a target point on thetherapeutic target, and rotates the magnetic tool at a frequencysufficient to cut through the therapeutic target. The magnet can bepositioned so that poles of the magnet periodically attract the opposingpoles of the magnetic tool during rotation, and the magnetic tool ispushed towards the therapeutic target by a stabilizing rod upon whichthe magnetic tool rotates. In some aspects, the magnet can be positionedso that the poles of the magnet continuously attract the opposing polesof the magnetic tool during rotation, and the magnetic tool is pulledtowards the therapeutic target by an attractive force (e.g., a directedgradient) of the magnet.

In some embodiments, a system is provided for increasing fluid flow in acirculatory system comprising a magnet having a magnetic field forcontrolling magnetic rotors in the fluid, a display for displaying, to auser, the magnetic rotors and the therapeutic target in the fluid, and acontroller that, in response to instructions from the user, controls themagnetic field to: (a) position the magnetic rotors adjacent to thetherapeutic target, (b) adjust an angular orientation of the magneticrotors with respect to the therapeutic target, and (c) rotate and movethe magnetic rotors through the fluid in a generally circular motion tomix the fluid and substantially clear the therapeutic target.

In various embodiments, the display can display real time (e.g.,streaming) video of the magnetic rotors and the therapeutic target, andthe display can superimpose a graphic representative of a rotation planeof the magnetic field and another graphic representative of theattractive force (e.g., directed gradient) of the magnetic field on thereal time video on the display. In some aspects, the magnet can be apermanent magnet coupled to a motor and a movable arm, and thecontroller can include a remote control device for a user to manipulatethe position, rotation plane and/or rotation frequency of the magneticfield with respect to the therapeutic target. The remote control devicecan be used to manipulate the position and rotation plane in one, two,or three dimensions. In some aspects, the real time video can correspondto images received from an imaging system, such as a transcranialDoppler imaging system, a PET imaging system, an x-ray imaging system,an MRI imaging system, a CT imaging system, an ultrasound imagingsystem, and/or the like. In some embodiments, the imaging system isrelatively immune from the magnetic fields present when the controlsystem is in operation. The control system can receive images from theimaging system, register the images, and present them to the user toprovide real-time feedback as to the position of the magneticnanoparticles, vasculature of the patient, and/or the location of thetarget object. In some embodiments, imaging the magnetic nanoparticlescan provide information about drug infusion and/or dose concentration.Using this information, the control of the magnetic nanoparticles can bealtered between a mode where nanoparticles are collected, and a modewhere nanoparticles are vortexed, or made to follow a substantiallycircular path to better mix the chemical agent within the vasculature,thereby enhancing diffusion of the chemical agent to the location of thetherapeutic target and/or to enhance interaction of the chemical agentwith the therapeutic target. In some embodiments, the magneticnanoparticles can include a contrast agent or tracer and can becorrelated to a drug or chemical agent. In some embodiments, themagnetic nanoparticles are used as an indication of the amount ofdiffusion within the vasculature in a region of the therapeutic target.

In some embodiments, the display can adjust the graphics in response toinstructions received from the user through the remote control device.In various aspects, the magnet can be an electro-magnet coupled to amotor and a movable arm, and the controller can perform image processingto identify the location, shape, thickness and density of thetherapeutic target, and can automatically manipulate the movable arm tocontrol the position, rotation plane and/or rotation frequency of themagnetic field to clear the therapeutic target. In some aspects, theautomatic manipulation can control the nanoparticles according to anavigation route designated or programmed by a user. The user candetermine and input the navigation route and make adjustments duringparticle infusion or at any other time during a therapeutic procedure.In some aspects, the navigation route can be automatically calculatedand/or adjusted by a controller of the therapeutic system.

In some embodiments, the automatic manipulation allows the magneticsystem to be stowed in a substantially shielded enclosure, therebysubstantially reducing or preventing magnetic fields of one or moremagnets of the system from having an effect on persons or items outsidethe system. For example, the system can include an enclosure made out ofa suitable shielding material (e.g., iron). The automatic manipulationprovided by the controller can move the one or more magnets of thesystem into the shielded enclosure when not in use.

In some embodiments, the therapeutic system provides real-timeinformation for the improved control of movement of the magneticnanoparticles. The magnetic nanoparticles can be configured to bedetectable with an imaging modality. For example, the magneticnanoparticles may be attached to a contrast or nuclear agent to bevisible using an x-ray-based system or PET scanner, respectively. Otherimaging modalities can include Doppler imaging (e.g., transcranialDoppler), which may detect the fluidic current through vasculaturecreated by the magnetic nanoparticles, or ultrasound-based diagnosticimaging systems, which may provide direct two-dimension orthree-dimensional imaging. Combining the control system with an imagingsystem can provide the ability to track the infusion of the chemicaladjunct in real-time into low-blood-flow lumens. By manipulating themagnetic system, three-degrees of control of the infused magneticnanoparticles can be achieved, thereby improving the ability to directthe therapy.

The imaging modality can be any modality, including imaging modalitiescapable of resolving a device or chemical agent which is affected by thefluidic current generated by the magnetic nanoparticles. The imagingmodality, in one embodiment, images an area of interest and providesmetric information. The therapeutic system can include a communicationmodule for communicating imaging data to an external device (such as adisplay device or a storage device). The therapeutic system can includea registering module for registering the reference frame of the image tothe reference frame of the magnetic system. The system can then receivethe image, register the image, track the magnetic nanoparticles, andprovide a means of directing the nanoparticles to be navigated along adesired path, either by an operator or automatically by a controller ofa computing device. The imaging data can be two- or three-dimensionaldata. Three-dimensional information could be advantageous wherenavigational control occurs in three dimensions. In some embodiments,the control of the magnetic nanoparticles can occur remotely using thesystems described herein.

In certain embodiments, the magnetic rotors can be formed by magneticnanoparticles which combine in the presence of the magnetic field (e.g.,to form a chain of nanoparticles). In some aspects, the fluid can be amixture of blood and a therapeutic agent (e.g., a thrombolytic drug),the blood and therapeutic agent being mixed by the generally circularmotion of the magnetic rotors to erode and clear a therapeutic target.In some aspects, the generally circular motion of the magnetic rotorscan redirect the therapeutic agent from a high flow blood vessel to alow flow blood vessel which contains the therapeutic target.

In one embodiment, a method is also provided for increasing fluid flowin a circulatory system comprising: (a) administering a therapeuticallyeffective amount of magnetic rotors to the circulatory system of apatient having a fluid obstruction, and (b) applying a magnet to thepatient, the magnet having a magnetic field and a gradient forcontrolling the magnetic rotors in a circulatory system, and (c) using acontroller for positioning and rotating the field and the gradient in amanner to agglomerate and move the magnetic rotors with respect to atherapeutic target in the circulatory system of the patient, whereincontact of the therapeutic target with a therapeutic agent (e.g., apharmaceutical composition) in the circulatory system is increased andfluid flow is increased.

The therapeutic agent (e.g., pharmaceutical composition, chemicaladjunct), according to several embodiments, can be attached to themagnetic rotor or to the individual magnetic nanoparticles comprisingthe magnetic rotor. For example, the magnetic nanoparticles can includea coating to facilitate attachment of therapeutic agents. Thetherapeutic agent can be administered to the circulatory system of thepatient separate from the magnetic rotors. In various embodiments, thetherapeutic agent is a thrombolytic drug.

In some embodiments, the magnet can be a permanent magnet rotatablycoupled to a motor, and the controller can control the motor to positionthe magnet at an effective distance and an effective orientation planewith respect to the therapeutic target, and can rotate the magnet at aneffective frequency to cause the magnetic rotors to travel within thevasculature toward the therapeutic target. In some embodiments, themagnet can be an electromagnet having a magnetic field strength andmagnetic field polarization driven by electrical current, and thecontroller can position the electromagnet at an effective distance andan effective orientation plane with respect to the therapeutic target,and can rotate the magnetic field of the electro-magnet by adjusting theelectrical current.

The system of the method, according to several embodiments, can furtherinclude a display for viewing the magnetic rotors and therapeutictarget, and a user interface for controlling the magnetic rotors,wherein a user controls the magnetic rotors to increase contact of thetherapeutic target with a therapeutic agent (e.g., a pharmaceuticalcomposition, chemical adjunct, stem cell, anti-cancer agent,anti-angiogenesis agent) in the circulatory system by adjusting afrequency of the rotating magnetic field, a plane of the rotatingmagnetic field with respect to the therapeutic target, and/or a distanceof the rotating magnetic field with respect to the therapeutic target.

The therapeutic target, according to several embodiments, can be athrombosis (e.g., a clot) in a human blood vessel (e.g., a blood vesselof the brain or leading to the brain or a blood vessel in a leg). Insome aspects, the magnetic rotors can be formed from magneticnanoparticles injected into the circulatory system. The therapeutictarget, in one embodiment, is a full or partial blockage of a veinbivalve. In certain aspects, the magnetic rotors move through the fluidin a generally circular motion by repeatedly (a) walking end over endalong the blood vessel away from the magnetic field in response to therotation of the rotors and an attractive force of the magnetic field,and (b) flowing back through the fluid towards the magnetic field inresponse to the rotation of the rotors and the attractive force of themagnetic field.

The rotor, according to several embodiments, is a magnetic nanoparticleof a diameter greater than or equal to about 10 nm and/or less than orequal to about 200 nm, including but not limited to from about 10 nm toabout 150 nm, from about 15 nm to about 100 nm, from about 20 nm toabout 60 nm, from about 20 nm to about 100 nm, from about 30 nm to about50 nm, overlapping ranges thereof, less than 200 nm, less than 150 nm,less than 100 nm, less than 60 nm. In some aspects, the therapeutictarget is a vascular occlusion in the patient's head or a vascularocclusion in the patient's leg.

In some embodiments, a method is provided for increasing drug diffusionin a circulatory system comprising (a) administering a therapeuticallyeffective amount of magnetic rotors to the circulatory system of apatient, (b) applying a magnet to the patient, the magnet having amagnetic field and a gradient for controlling the magnetic rotors in acirculatory system, and (c) using a controller configured to positionand rotate the field and the gradient in a manner to agglomerate andmove the magnetic rotors with respect to a therapeutic target in thecirculatory system of the patient, wherein diffusion of a therapeuticagent (e.g., a pharmaceutical composition) in the circulatory system atthe therapeutic target is increased.

In accordance with several embodiments, a method of treating a thrombuswithin a blood vessel of the brain through external magnetomotivemanipulation of magnetic nanoparticles is provided. The method cancomprise introducing a thrombolytic drug within vasculature of asubject, the thrombolytic drug configured to have a therapeutic effecton a thrombus within a blood vessel of the brain. In some embodiments,the method comprises introducing a plurality of coated magneticnanoparticles within the vasculature of the subject. The magneticnanoparticles may have a diameter between about 15 nm and 150 nm,between about 20 nm and 200 nm, between about 10 nm and about 170 nm, oroverlapping ranges thereof.

In some embodiments, the method comprises orienting a permanent magnetexternal to the blood vessel and having a magnetic field and a directedmagnetic gradient to establish a magnetic rotation plane of thepermanent magnet. The method may comprise programming a controller tocause the permanent magnet to be positioned and to rotate in a mannersufficient to cause the magnetic nanoparticles to agglomerate to form aplurality of magnetic nanoparticle rods having a length between 0.1 and2 millimeters within the vasculature to travel toward the thrombus in anend over end motion in response to torque exerted by the rotatingmagnetic field and to an attractive force of the directed magneticgradient.

In some embodiments, the rotational frequency of the rotating magneticfield is between 0.1 Hz and 30 Hz, between 1 Hz and 20 Hz, between 2 Hzand 10 Hz or overlapping ranges thereof. In some embodiments, therotating magnetic field has a magnitude of between 0.01 Tesla and 0.1Tesla, between 0.1 Tesla and 0.5 Tesla, between 0.05 Tesla and 1 Tesla,or overlapping ranges thereof. In some embodiments, the directedmagnetic gradient has a strength of between 0.01 Tesla/meter and 5Tesla/meter, between 0.05 Tesla/meter and 3 Tesla/meter, between 0.1Tesla/meter and 2 Tesla/meter, or overlapping ranges thereof.

In some embodiments, the rotation of the magnet causes the magneticnanoparticle rods to generate a circulating fluid motion within thevasculature proximal to the thrombus. The circulating fluid motion canfacilitate (e.g., increase) contact of the thrombolytic drug with thethrombus by enhancing diffusion of the thrombolytic drug to the regionof the blood vessel proximal to the thrombus and by refreshing contactof the thrombus with the thrombolytic drug (e.g., with drug that has notyet interacted with the thrombus), thereby providing more effectiveinteraction of the thrombolytic drug with the thrombus.

In some embodiments, the thrombolytic drug is attached to the magneticnanoparticles prior to introduction. In some embodiments, thethrombolytic drug is introduced within the vasculature separate from themagnetic nanoparticles. The permanent magnet can be coupled (e.g.,rotatably) to a motor by a movable arm. In some embodiments, introducinga thrombolytic drug within vasculature of a subject comprisesintroducing a reduced dose of the thrombolytic drug than would beintroduced if the magnetic nanoparticles were not introduced. In someembodiments, causing the magnetic nanoparticle rods to generate acirculating fluid motion within the vasculature proximal to the thrombuscomprises adjusting the rotational frequency of the rotating magneticfield, a plane of the rotating magnetic field with respect to thethrombus, and/or a distance of the rotating magnetic field with respectto the thrombus.

In some embodiments, the method comprises adjusting one or more of theposition, the rotation plane and the rotation frequency of the magneticfield in response to at least one characteristic of the thrombus. Thecharacteristic of the thrombus can be a location, a shape, a thickness,a density, or other characteristic of the thrombus. In some embodiments,the characteristic is determined from one or more images of the regionof the blood vessel in which the thrombus is located. In someembodiments, orienting a permanent magnet having a magnetic field and adirected magnetic gradient to establish a magnetic rotation plane of thepermanent magnet is performed based on preoperative images of the bloodvessel.

In accordance with several embodiments, a system for treating a fluidobstruction through external magnetomotive manipulation of magneticnanoparticles introduced within vasculature of a subject is provided. Insome embodiments, the system comprises a plurality of coated magneticnanoparticles configured to be introduced within vasculature of asubject. The system can comprise a magnetomotive device configured toprovide external manipulation of the magnetic nanoparticles within thevasculature.

In some embodiments, the magnetomotive device comprises a platform and adrive motor coupled to the platform by a motor support structure. Insome embodiments, the magnetomotive device comprises a rotatable flangecoupled to the drive motor. The rotatable flange can be coupled to thedrive motor in a manner such that, in use, the drive motor rotates therotatable flange about a central drive axis of the device or system. Insome embodiments, a distal end of the rotatable flange comprises amounting portion and a mounting plate coupled to the mounting portion.In some embodiments, a permanent magnet is coupled to the mounting platesuch that, in use, the magnet rotates about the central drive axis ofthe magnetomotive device to provide a rotating, time-varying magneticfield and a directed magnetic gradient that controls movement of themagnetic nanoparticles introduced within vasculature of a subject. Insome embodiments, the system comprises a controller that, in use, causesthe drive motor to manipulate the movable arm (a) to control theposition, rotation plane and rotation frequency of the magnetic field ofthe magnet and (b) to control the direction of the magnetic gradient ofthe magnet. In some embodiments, the controller positions and rotatesthe magnetic field and directs the magnetic gradient in a mannersufficient to cause the magnetic nanoparticles to agglomerate into aplurality of magnetic nanoparticle rods. The time-varying magnetic fieldand the directed magnetic gradient can cause the magnetic nanoparticlerods to generate a circulating fluid motion within a blood vesselproximal to a fluid obstruction that facilitates contact of atherapeutic agent introduced within the blood vessel with the fluidobstruction.

In some embodiments, the permanent magnet is a rectangular solid. Theface of the magnet in which the North and South poles reside can befastened to the mounting plate. The magnet can be coupled to themounting portion at the distal end of the rotatable flange such that, inuse, the magnetic field rotates parallel to a front face of the magnet.In some embodiments, the magnetic nanoparticle rods travel through theblood vessel by repeatedly a) walking end over end along the bloodvessel away from the magnetic field in response to rotation of themagnetic nanoparticle rods caused by torque of the time-varying magneticfield and the directed magnetic gradient; and b) flowing back throughfluid in the blood vessel towards the magnetic field in response to therotation of the magnetic nanoparticle rods caused by torque of thetime-varying magnetic field and the directed magnetic gradient. In someembodiments, a portable magnetomotive system for increasing fluid flowthrough an obstructed blood vessel by wireless manipulation of magneticnanoparticles is provided that comprises a magnet pod and a headrestrotatably coupled to the magnet pod. The headrest, in use, can define aposition and attitude of a subject's head in relation to the magnet pod.A rail attachment can be attached to the magnet pod that, in use,substantially secures the magnet pod to a rail or other supportstructure of a bed or other patient transport or occupancy unit. Theportable magnetomotive system can comprise a magnet coupled to themagnet pod, the magnet having a magnetic field and a directed magneticgradient that, in use, provides external magnetomotive control ofmagnetic nanoparticles introduced within vasculature of a subject.

In some embodiments, the magnetic nanoparticles comprisesuperparamagnetic iron oxide nanoparticles. In some embodiments, themovable arm is composed of nonmagnetic material and the movable armpasses through a first bearing and a second bearing adapted tofacilitate smooth rotation of the movable arm, the first bearing and thesecond bearing being affixed to a platform by a bearing mountingstructure. In some embodiments, the platform is suspended by asuspension arm that is coupled to an arm positioner of a portable baseby a suspension arm attachment joint. In use, the suspension armattachment joint is configured to allow rotation of the magnetomotivedevice about the end of the arm positioner coupled to the suspension armattachment joint.

In some embodiments, the magnetomotive device comprises two motors, witha first motor adapted to rotate around a first axis to cause rotation ofthe magnet and a second motor adapted to rotate around a second axis toset the orientation of the rotation plane. In some embodiments, thetherapeutic agent comprises a thrombolytic agent such as tissueplasminogen activator (tPA). The fluid obstruction can be an arterialthrombus in a cerebral blood vessel.

These and other features, aspects and advantages of the disclosure willbecome better understood with reference to the following description,examples and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

Those of skill in the art will understand that the drawings, describedbelow, are for illustrative purposes only. The drawings are not intendedto limit the scope of the disclosure in any way.

FIGS. 1A and 1B illustrate an example of a permanent-magnet statorsystem whose magnet's North-South pole rotates in a plane parallel tothe system's front face, which is driven by a single motor.

FIG. 2 illustrates a portable positioner cart to which the magnet systemof FIGS. 1A and 1B can be attached.

FIG. 3 illustrates an example of a permanent-magnet stator system whosemagnet's North-South pole rotates in a plane perpendicular to thesystem's front face, which is driven by a single motor.

FIGS. 4A and 4B illustrate an example of a permanent-magnet statorsystem driven by two motors, allowing the magnet to be rotated in anyplane.

FIG. 5 illustrates an example of a three-electromagnet stator system,with power supplies, attached to an arm positioner.

FIG. 6 illustrates an embodiment of a portable magnetic pod with a railattachment capable of being attached to a bedside rail of a bed.

FIGS. 7A to 7C illustrate various embodiments of a user controlinterface for a magnetomotive stator system.

FIG. 8 illustrates an embodiment of a control process.

FIG. 9A illustrates the manipulation of magnetic nanoparticles to createmotion within a blood vessel, in accordance with an embodiment of theinvention.

FIG. 9B illustrates the action of the magnetic field on a magneticnanoparticle to create rotation, in accordance with an embodiment of theinvention.

FIG. 9C illustrates the magnetic manipulation of a magnetic nanoparticledistribution inside a fluid-filled enclosure to create flow patterns, inaccordance with an embodiment of the invention.

FIG. 9D illustrates the magnetic manipulation of a magnetic nanoparticledistribution to amplify the effects of therapeutic agents on a clot, inaccordance with an embodiment of the invention.

FIG. 10 illustrates an embodiment of a method for controlling magneticnanoparticles.

FIG. 11 illustrates the manipulation of a magnet to cross a vesselocclusion, in accordance with an embodiment of the invention.

FIGS. 12A and 12B illustrate an example method of use of a magnetomotivestator system and magnetic nanoparticles for the treatment of a vascularocclusion in the brain, in accordance with an embodiment of theinvention.

FIGS. 13A-13E illustrate a model for the enhanced diffusion oftherapeutic drugs in an area of complete blockage having no fluid flow,in accordance with an embodiment of the invention, where (A) shows avessel having no drug, (B) shows the addition of a drug to the system(shown in grey), but the inability to mix at the site of the blockage,(C) shows the addition of magnetic nanoparticles to the system that aredrawn to the blockage site via a magnet (not shown), (D) showsturbulence created by applying the magnetic field and gradient in atime-dependent fashion and mixing the drug to come closer to contactingthe blockage site, and (E) showing completed diffusion of the drug andcontact at the blockage site via mixing using the magneticnanoparticles.

FIG. 14 illustrates an embodiment of the magnetomotive stator system.

FIG. 15 illustrates an embodiment of the magnetomotive stator system.

FIG. 16A is a cross sectional drawing displaying a representativetargeted region of a blocked lumen with no flow, under conventionaltreatment.

FIG. 16B is a cross sectional drawing of a targeted region having bloodflow, but with ineffective drug clearance using standard drug delivery.

FIGS. 17A-17C illustrate arranged structuring of magnetic nanoparticlesto create rods as used in procedures according to some embodiments,where (A) shows unorganized nanoparticles in zero field, (B) shows asmall field applied to the nanoparticles and organization into “rods,”and (C) shows a larger field applied to the nanoparticles.

FIG. 18 is a plot of nanoparticle agglomerate rod length as a functionof the applied magnetic field, showing a limiting length, in accordancewith an embodiment of the invention.

FIG. 19 illustrates a sequence of end over end motions leading totranslation of magnetic rods formed from a plurality of magneticnanoparticles, in accordance with an embodiment of the invention.

FIGS. 20A and 20B illustrate a characteristic saturation ofnanoparticles with increased density as a result of rotating motionleading to a buildup of magnetic nanoparticles.

FIGS. 21A and 21B illustrate a derivation of the physics of elements andfields leading to magnetic torque on a nanoparticle rod, in accordancewith an embodiment of the invention.

FIG. 21C illustrates the distribution of kinetic energy as a function offrequency of rotation of the rods, in accordance with an embodiment ofthe invention.

FIG. 22A illustrates the introduction of turbulence with spinning rodsin a vessel with no flow, to treat the occlusion problem shown in FIG.16A, in accordance with an embodiment of the invention.

FIG. 22B exhibits motion and effect of drug delivery according to someembodiments for introduction of turbulence in the occluded flow categoryshown in FIG. 16B, in accordance with an embodiment of the invention.

FIG. 23A is a cross section view of a group of rotating rods in agenerally circular motion against a total occlusion in a vessel, inaccordance with an embodiment of the invention.

FIG. 23B is a cross section view of the rotation of rods starting toform a ball, in accordance with an embodiment of the invention.

FIG. 23C is a cross section view of the rotating ball of rods and clotmaterial having opened the obstructed vessel, in accordance with anembodiment of the invention.

FIG. 23D is a cross section view of the ball of FIG. 23C being removedby a small magnet on a guide wire, in accordance with an embodiment ofthe invention.

FIG. 24 is a cross section view of a vessel with rotating magneticcarriers applying therapeutic agents to safely remove occluding materialon a valve leaflet in a blood vessel, in accordance with an embodimentof the invention.

FIG. 25 illustrates the result of end over end motion of a magnetic rod“walk” along a path to a distant clot in a complex vessel, in accordancewith an embodiment of the invention.

FIGS. 26A and 26B illustrate the generation of motion of amagnetically-enabled thrombectomy device which is depicted as a sphere,where (A) shows no field or gradient applied and (B) shows a field andgradient applied causing the sphere to move laterally, in accordancewith an embodiment of the invention.

FIGS. 27A-27D illustrate the use of a rotating magnetically-enabledthrombectomy sphere to address an occluded vessel, in accordance with anembodiment of the invention. FIG. 27A is a cross section view of arotating magnetically-enabled thrombectomy sphere in circular motionagainst a total occlusion in a vessel. FIG. 27B is a cross section viewof the magnetically-enabled thrombectomy sphere wearing away the surfaceof the occlusion. FIG. 27C is a cross section view of themagnetically-enabled thrombectomy sphere having opened the obstructedvessel. FIG. 27D is a cross section view of the magnetically-enabledthrombectomy sphere being removed by a small magnet on a guide wire.

FIG. 28A is a cross section view illustrating a tetheredmagnetically-enabled thrombectomy sphere having opened an obstructedvessel, in accordance with an embodiment of the invention.

FIG. 28B illustrates an embodiment of a tethered magnetically-enabledthrombectomy sphere in which the tether runs through the magneticsphere's rotational axis.

FIG. 28C is another example tether embodiment which loops around themagnet's rotational axis, in accordance with an embodiment of theinvention.

FIG. 29 is a cross section view of a rotating magnetically-enabledthrombectomy sphere in circular motion against plaque on vessel walls,in accordance with an embodiment of the invention.

FIG. 30A illustrates the result of end over end motion of a magnetic rodor magnetic ball “walk” along a path to a distant clot in a complexvessel as imaged by an imaging technology, in accordance with anembodiment of the invention.

FIG. 30B illustrates the ability to recreate the path based on themeasurements made in FIG. 30A.

FIG. 31 illustrates an embodiment of an infusion system havingmicro-bore tubing.

FIGS. 32A and 32B illustrate embodiments of infusion systems havingultrasonic transducers to maintain dispersion of an infusate.

FIG. 33 illustrates an embodiment of an infusion system employingmagnetic energy to maintain dispersion of an infusate.

FIG. 34 illustrates an embodiment of an infusion system having amechanical agitation system configured to maintain dispersion of aninfusate.

FIG. 35 illustrates an embodiment of an infusion system employingmultiple bolus cartridges.

FIGS. 36A and 36B illustrate an embodiment of an infusion systememploying fluid dynamic mixing to maintain dispersion of an infusate.

FIGS. 37A and 37B illustrate the clearance of a thrombosis in the veinof a rabbit using embodiments of the magnetomotive stator system andmagnetic nanoparticles.

FIG. 38 illustrates the dosage response curve of tPA using embodimentsof the magnetomotive stator system showing both reduced time to increaseblood flow in a rabbit, and reduced amount of tPA required to producethe same result, in accordance with an embodiment of the invention.

FIG. 39 illustrates results of testing showing that concentrating a drugusing magnetic nanoparticles is faster than diffusion alone.

FIG. 40 illustrates a graph of blood flow as a function of time for anexample of magnetic nanoparticle-accelerated clot lysis.

FIG. 41 illustrates an example of bifurcated nanoparticle control usinga parent vessel.

FIG. 42 illustrates an example of lysis of biological thrombus usingstreptokinase and magnetic nanoparticles.

FIG. 43 illustrates graphs of streptokinase and tPA dose responseimprovements.

FIG. 44 illustrates an example test tube setup having defined tPA doseand relative magnetic nanoparticle dose.

FIG. 45 illustrates a graph of lysis rate as a function of relativemagnetic nanoparticle dose.

DETAILED DESCRIPTION Abbreviations and Definitions

The scientific and technical terms used in connection with thedisclosure shall have their ordinary meanings (e.g., as commonlyunderstood by those of ordinary skill in the art) in addition to anydefinitions included herein. Further, unless otherwise required bycontext, singular terms shall include pluralities and plural terms shallinclude the singular. The disclosures of The McGraw-Hill Dictionary ofChemical Terms (Parker, S., Ed., McGraw-Hill, San Francisco (1985)) andFerrohydro-Dynamics (R. E. Rosensweig, Dover Publications, New York,(1985)) are hereby expressly incorporated by reference herein.

“Patient” shall be given its ordinary meaning and shall include, withoutlimitation, human and veterinary subjects.

“Thrombolytic drug” shall be given its ordinary meaning and shallinclude without limitation drugs capable of degrading a blood clot orarteriosclerotic plaque. For example, a thrombolytic drug can includetissue plasminogen activator (tPA), plasminogen, streptokinase,urokinase, recombinant tissue plasminogen activators (rtPA), alteplase,reteplase, tenecteplase, and other drugs, and can include these drugsadministered alone or co-administered with warfarin and/or heparin.

“Magnetic nanoparticle” shall be given its ordinary meaning and shallinclude without limitation a coated or uncoated metal particle having adiameter greater than or equal to about 1 nm and/or less than or equalto about 1000 nm, greater than or equal to about 10 nm and/or less thanor equal to about 200 nm, greater than or equal to about 15 nm and/orless than or equal to about 150 nm, greater than or equal to about 20 nmand/or less than or equal to about 60 nm, 80 nm, 100 nm, and all integervalues between 1 nm and 1000 nm, e.g., 1, 2, 3, 4, 5, . . . 997, 998,999, and 1000. The appropriate sizes of magnetic nanoparticles candepend on the therapeutic target of the system (e.g., very small vesselscan accept smaller nanoparticles and larger parts of a circulatorysystem can accept larger nanoparticles). Examples of such magneticnanoparticles include superparamagnetic iron oxide nanoparticles. Thenanoparticles may be made of magnetite or other ferromagnetic mineral oriron oxide and, in some embodiments, can be coated with any one or acombination of the following materials: (1) coatings which enhance thebehavior of the nanoparticles in blood by making them either hydrophilicor hydrophobic; (2) coatings which buffer the nanoparticles and whichoptimize the magnetic interaction and behavior of the magneticnanoparticles; (3) contrast agent or agents which allow visualizationwith magnetic resonance imaging, X-ray, Positron Emission Tomography(PET), ultrasound, or other imaging technologies; (4) therapeutic agentswhich accelerate destruction of a circulatory system blockage; (5) stemcells, anti-cancer drugs, and/or anti-angiogenesis drugs; and (6)thrombolytic drugs. Examples of both coated and uncoated magneticnanoparticles and methods of making such magnetic nanoparticles caninclude, for example, those described in U.S. Pat. Nos. 5,543,158,5,665,277, 7,052,777, 7,329,638, 7,459,145, and 7,524,630, the entiredisclosure of each of which is hereby expressly incorporated byreference herein. See also Gupta et al., Biomaterials, Volume 26, Issue18, June 2005, Pages 3995-4021, the disclosure of which is herebyexpressly incorporated by reference herein.

“Fluid obstruction” shall be given its ordinary meaning and shallinclude without limitation a blockage, either partial or complete, thatimpedes the normal flow of fluid through a circulatory system, includingthe venous system, arterial system, central nervous system, andlymphatic system. “Vascular occlusions” are fluid obstructions thatinclude, but are not limited to, atherosclerotic plaques, fatty buildup,arterial stenosis, restenosis, vein thrombi, cerebral thrombi,embolisms, hemorrhages, other blood clots, and very small vessels.Sometimes, fluid obstructions are generally referred to herein as“clots.”

“Substantially clear” shall be given its ordinary meaning and shallinclude without limitation removal of all or part of a fluid obstructionthat results in increased flow of fluid through the circulatory system.For example, substantially clearing the vein includes creating a pathwaythrough or around a thrombus that blocks a blood vessel so that bloodcan flow through or around the thrombus.

“Very small vessel” shall be given its ordinary meaning and shallinclude without limitation a circulatory system fluid pathway having adiameter from about 1 μm to about 10 μm.

“Increased fluid flow” shall be given its ordinary meaning and shallinclude without limitation increasing the throughput of a blockedcirculatory system from zero to something greater than zero. Forexample, in flowing circulatory systems, the term increased fluid flowcan mean increasing the throughput from a level prior to administrationof one or more magnetic nanoparticles in a patient to a level greaterthan the original fluid flow level.

“Agglomerate” shall be given its ordinary meaning and shall includewithout limitation rotational clustering and chaining of a group ofindividual magnetic rotors in a manner to develop “rods” from themagnetic nanoparticles (for example, as described herein with respect toFIG. 17). Such a group of rotating rotors forms an ensemble in whichindividual rotors generally rotate simultaneously and travel in the samedirection as a group. The application of the combined magnetic field andgradient over time is the manner of assembling the rods. Such a groupcomprises characteristics that can different than what can be expectedof individual rotors acting alone and can create hydrodynamic forces ina fluid stream or still fluid to create turbulence or enhance thediffusion of a composition or liquid in the fluid stream or still fluid.

“Treatment” shall be given its ordinary meaning and shall includewithout limitation an approach for obtaining beneficial or desiredclinical results. For purposes of this disclosure, beneficial or desiredclinical results include, but are not limited to, one or more of thefollowing: improvement or alleviation of any aspect of fluid obstructionin the circulatory system including, but not limited to, fluidobstructions (e.g., stroke, deep vein thrombosis), coronary arterydisease, ischemic heart disease, atherosclerosis, and high bloodpressure.

“Drug, compound, or pharmaceutical composition” shall be given theirordinary meanings and shall include without limitation a chemicalcompound or composition capable of inducing a desired therapeutic effectwhen properly administered to a patient, for example enzymaticdegradation of a thrombus or atherosclerotic plaque.

“Effective amount” shall be given its ordinary meaning and shall includewithout limitation an amount of a therapeutic agent (e.g., drug,chemical adjunct, compound or pharmaceutical composition) sufficient toeffect beneficial or desired results including clinical results such asalleviation or reduction in circulatory system fluid blockage. Aneffective amount can be administered in one or more administrations. Forexample, an effective amount of drug, compound, or pharmaceuticalcomposition can be an amount sufficient to treat (which includes toameliorate, reduce incidence of, delay and/or prevent) fluid blockage inthe circulatory system, including vascular occlusions in the head andextremities. The effective amount of a therapeutic agent can includecoated or uncoated magnetic nanoparticles formulated to be administeredto a patient. The effective amount may be considered in the context ofadministering one or more therapeutic agents, and a single agent may beconsidered to be given in an effective amount if, in conjunction withone or more other agents, a desirable result may be or is achieved.

“Reducing incidence” shall be given its ordinary meaning and shallinclude without limitation any of reducing severity (which can includereducing need for and/or amount of (e.g., exposure to) drugs and/ortherapies generally used for these conditions, including, for example,tPA), duration, and/or frequency (including, for example, delaying orincreasing time to displaying symptoms of circulatory system blockage).For example, individuals may vary in terms of their response totreatment, and, as such, for example, a method of reducing incidence offluid blockage in a patient reflects administering the effective amountof the magnetic nanoparticles, whether or not in combination with atherapeutic agent, based on a reasonable expectation that suchadministration may likely cause such a reduction in incidence in thatparticular individual.

“Ameliorating” one or more symptoms of circulatory system blockage shallbe given its ordinary meaning and shall include without limitation alessening or improvement of one or more symptoms of circulatory systemblockage as compared to not administering a magnetic nanoparticle,whether or not in combination with a therapeutic agent, using the systemdescribed herein. Ameliorating can also include shortening or reducingin duration a symptom.

“Delaying” the development of a symptom related to circulatory systemblockage shall be given its ordinary meaning and shall include withoutlimitation to defer, hinder, slow, retard, stabilize, and/or postponeprogression of the related symptoms. This delay can be of varyinglengths of time, depending on the history of the disease and/orindividuals being treated. For example, a sufficient or significantdelay can, in effect, encompass prevention in that the individual doesnot develop symptoms associated with circulatory system blockage. Amethod that delays development of the symptom is a method that reducesprobability of developing the symptom in a given time frame and/orreduces extent of the symptoms in a given time frame, when compared tonot using the method. Such comparisons may be based on clinical studies,using a statistically significant number of subjects.

“Pharmaceutically acceptable carrier” shall be given its ordinarymeaning and shall include without limitation any material which, whencombined with a magnetic nanoparticle and/or an active ingredient, isnon-reactive with the subject's immune system and allows the activeingredient to retain biological activity. For example, pharmaceuticallyacceptable carriers include pharmaceutical carriers such as a phosphatebuffered saline solution, water, emulsions such as oil/water emulsion,and various types of wetting agents. Examples of diluents for parenteraladministration are phosphate buffered saline or normal (0.9%) saline.

“Pharmaceutically acceptable” shall be given its ordinary meaning andshall include without limitation being approved by a regulatory agencyof the Federal or a state government or listed in the U.S.Pharmacopoeia, other generally recognized pharmacopoeia in addition toother formulations that are safe for use in animals, and moreparticularly in humans and/or non-human mammals.

Overview of Magnetomotive Stator System and Methods for Wireless Controlof Magnetic Rotors

Systems and methods are described for the physical manipulation of freemagnetic rotors using a remotely placed magnetic field-generating statoraccording to several embodiments. Some embodiments of the inventionrelate to the control of magnetic nanoparticles to increase contact of atherapeutic target in a circulatory system with a therapeutic agent(e.g., a pharmaceutical compound, a thrombolytic drug), which can resultin increased fluid flow and the substantial clearance of fluid blockagesof the circulatory system. In various aspects, the system enhancesdiffusion of the therapeutic agent and uses permanent magnet-based orelectromagnetic field-generating stator sources. Magnetic fields andgradients can be used to act on magnetic nanoparticle agglomeratesand/or magnetic thrombectomy devices to reduce circulatory systemblockages, including vascular occlusions, in a patient. In variousaspects, the system and methods described herein can be used to treatfluid blockages of the circulatory system in the head (in particular,the brain) and in the extremities of the body, such as the vasculatureof arms and legs.

Some embodiments of the invention provide for a magnetically producedscouring process generated by magnetic nanoparticles and/ormagnetically-enabled thrombectomy devices acting on fluid blockage incombination with the mechanically-enhanced dissolving or lytic processof the therapeutic agent (e.g., thrombolytic agent) that is used. Inaccordance with several embodiments, the magnetic actions are derivedfrom a rotating magnetic field from an external magnet source which alsoprovides a pulling magnetic gradient that is not rotating. This externalcontrol advantageously provides forces and actions on circulatory systemblockages generally without mechanical invasion of the location. Inaccordance with several embodiments, the systems and methods describedherein can greatly increase interaction of the therapeutic agent withthe target circulatory system blockage. The interaction may leaveresidue that can be collected magnetically in such a way as to leavevenous walls or valves undamaged in the process. Another feature of thesystems and methods described herein is the ability to use drug andstirring conditions so that substantially all of the residue that isremoved forms a small soft clump with the magnetic nanoparticles thatcan be captured by a tiny magnet on the tip of a guide wire. To achievethese features, the system can use a rotating magnetic field incombination with a directed magnetic gradient to act on magneticnanoparticles or magnetically-enabled fluid blockage clearing devices.

In some embodiments, the rotating magnetic field is generated bymechanically rotating a strong permanent magnet having an orientationthat rotates the field at the target site, and at the same time presentsa steady magnetic gradient in a desired direction. In some embodiments,two or more magnetic coils can be used with appropriate phasing toprovide rotating fields with a gradient. When three or more coils areused, at least two coils can have axes having some perpendicularcomponent to each other to provide additional magnetic spatial andtiming features. For instance, two coils can have perpendicular axes andone can employ current lagging the other by 90 degrees to create arotating field at the target position. A third coil can be located andoriented to provide appropriate gradients at the target site, as well asindependent functions such as modulation.

With electronic control of the currents, a wide array of fields andgradients can be applied with a large number of time-related events. Theapplication of a rotating field with a gradient to a slurry of magneticnanoparticles can provide a defined type of arrangement of the grouping:that is the “agglomeration” of magnetic nanoparticles that cause them toform aligned rods of approximately 2 mm in length or less.

For example, a field of about 0.02 Tesla at the target site, incombination with a gradient of about 0.4 Tesla/meter, can create anagglomeration of magnetic nanoparticles (e.g., separated nanoparticlerods of length varying approximately from one to two millimeters inlength). These agglomerates can remain largely intact in vitro and invivo, but can be sufficiently flexible to provide “soft brushing” whenrotated. It has been observed that on rotation the nanoparticle rods can“walk” along a surface in a vessel, and when in contact with a fluidblockage, such as a blood clot, can remove minute particles of the clotmaterial with the aid of the thrombolytic drug. The nanoparticle rodscan softly “scrub” off fractions of the clot material continuously, insome cases without residue components of significant size. In othercases, depending on the type and location of obstruction, the deliveryof therapeutic agents (e.g., thrombolytic drugs) can be timed so thatthe residue ends up in a soft small magnetic ball, which can be capturedmagnetically and removed. Ultrasound and other imaging technologies(e.g., radiography, magnetic resonance, nuclear medicine, photoacoustic, thermography, tomography) can be used to visualize theprogress of such scrubbing. For example, transcranial ultrasound imagingcould be used to confirm clot destruction visually in a cranial embolismor stroke. Contrast agents and other agents that enhance visualizationof the magnetic nanoparticles can also be used (e.g., iodine, barium,gadolinium). The imaging technologies can be transmit images to adisplay device to provide an operator real-time feedback so that theoperator can navigate or otherwise control movement of the magneticnanoparticles.

Using a rotating magnetic field and gradient apparatus, it has beenobserved that fields of 0.02 Tesla with gradients of 0.4 Tesla/meter atthe target site facilitate more precise control over the rotation of asmall magnetic ball approximately 1.5 mm in diameter. It has been foundthat with proper alignment of the magnetic gradient, the ball-likestructure can be made to navigate the vessels and increase drug mixingat the blockage. In a similar manner, coatings that comprisethrombolytic agents and/or surface features can be added to enhancedestruction of a blockage.

The numerical parameters used can vary, depending on the particularnature of the circulatory system blockage, the thrombolytic drug, and/orthe design of the magnetically-enabled thrombectomy devices. Rotationalfrequencies (e.g., greater than or equal to 0.1 Hz and/or less than orequal to 100 Hz, including but not limited to from about 1 Hz to about30 Hz, from about 3 Hz to about 10 Hz, from about 0.5 Hz to about 50 Hz,from about 1 Hz to about 6 Hz, from about 0.1 Hz to about 10 Hz, fromabout 5 Hz to about 20 Hz, from about 10 Hz to about 30 Hz, from about20 Hz to about 50 Hz, from about 40 Hz to about 70 Hz, from about 50 Hzto about 100 Hz, overlapping ranges thereof, less than 5 Hz, less than10 Hz, less than 20 Hz, less than 30 Hz, less than 40 Hz, less than 50Hz) can be effective with a range of magnetic field magnitudes that canbe generated by magnets (e.g., greater than or equal to 0.01 Teslaand/or less than 1 Tesla, including but not limited to from about 0.01Tesla to about 0.1 Tesla, from about 0.05 Tesla to about 0.5 Tesla, fromabout 0.1 Tesla to about 0.6 Tesla, from about 0.3 Tesla to about 0.9Tesla, from about 0.5 Tesla to about 1 Tesla, overlapping rangesthereof, less than 1 Tesla, less than 0.5 Tesla, less than 0.25 Tesla,less than 0.1 Tesla), all in a volume of about one cubic foot, or bycoils with somewhat larger volume. Gradient strength can be greater thanor equal to 0.01 Tesla/m and/or less than or equal to 10 Tesla/m,including but not limited to from about 0.01 Tesla/m to about 1 Tesla/m,from about 0.01 Tesla/m to about 3 Tesla/m, from about 0.05 Tesla/m toabout 5 Tesla/m, from about 1 Tesla/m to about 4 Tesla/m, overlappingranges thereof, less than 5 Tesla/m, less than 3 Tesla/m, less than 2Tesla/m, less than 1 Tesla/m). The gradient direction generally centerson the center of mass for a permanent magnet, and using an electromagnetcan center on one of the coils, and in combination, can center betweenone or more coils.

Fluid Blockages of the Circulatory System

Parts of the body where fluid blockages of the circulatory system occurinclude the blood vessels associated with the legs and the brain. Twomajor hydrodynamic properties of such blockage are observed in thevasculature: low blood flow or total blockage. In either case, existingmodes of delivery of drugs for dissolving occlusions at surfaces ormechanical removal of, for example, thrombus material cannot effectivelyclear a degraded and impeding layer on a clot surface to be removed toallow fresh drug interaction with an underlayer. This can result indangerous components moving downstream which can result in a moredangerous blockage or death. In a typical flow situation, there arelocations where the flow does not effectively penetrate or target theintended site. In other situations, it is not possible to navigate athrombectomy device to the target due to smallness (e.g., a very smallvessel) or complexity of the three-dimensional shape of the occludedvessel.

Different thrombolytic drugs can be used in the thrombolytic process.For example, streptokinase can be used in some cases of myocardialinfarction and pulmonary embolism. Urokinase can be used in treatingsevere or massive deep venous thrombosis, pulmonary embolism, myocardialinfarction and occluded intravenous or dialysis cannulas. TissuePlasminogen Activator (“tPA” or “PLAT”) can be used clinically to treatstroke. Reteplase can be used to treat heart attacks by breaking up theocclusions that cause them.

In the case of stroke, tPA is used successfully in many cases, but inmany cases the effect of the drug is to leave downstream residue inclumps large enough to cause further blockage and sometimes death. Inaddition, the normal thrombolytic dosage administered to patients isrelated to increased bleeding in the brain. In many cases, theeffectiveness of chemical interaction of the thrombolytic agent with theblockage is slow and inefficient, leaving incomplete removal of theblockage. In blockages in the extremities, mechanical means of stirringand guiding the drug are limited, often difficult, and can be dangerous.In many cases, venous valves in the region of the procedure are damagedor not made blockage-free in procedures currently used. Some embodimentsdescribed herein advantageously provide new systems and methods forsignificant improvements in dealing with these major obstacles intreating occlusions of the blood flow.

Magnetomotive Stator System

In accordance with several embodiments, a therapeutic system is providedcomprising (a) a magnet having a magnetic field and a gradient forcontrolling magnetic rotors in a circulatory system, and (b) acontroller for positioning and rotating the field and the gradient in amanner to agglomerate and/or traverse the magnetic rotors with respectto a therapeutic target in the circulatory system. Using the therapeuticsystem, contact of the therapeutic target with a pharmaceuticalcomposition in the circulatory system can be increased. In variousaspects, the pharmaceutical composition can be attached to the magneticrotor, and in other aspects can be administered to the circulatorysystem separate from the magnetic rotors. In certain instances, thepharmaceutical composition can be a thrombolytic drug.

Therapeutic targets of the system can include fluid obstructions suchas, but not limited to, atherosclerotic plaques, fibrous caps, fattybuildup, coronary occlusions, arterial stenosis, arterial restenosis,vein thrombi, arterial thrombi, cerebral thrombi, embolism, hemorrhage,very small vessels, other fluid obstructions, or any combination ofthese. Therapeutic targets of the system can also include any organ ortissue of the body. For example, therapeutic targets can be targetsidentified for stem cell or gene therapy. In various aspects, thecirculatory system is vasculature of a patient, in particular a humanpatient.

In various embodiments, the therapeutic system comprises a permanentmagnet coupled to a motor, and the controller controls a motor toposition the magnet at an effective distance and an effective plane withrespect to the therapeutic target, and rotates the magnet at aneffective frequency with respect to the therapeutic target. In variousembodiments, the therapeutic system comprises an electromagnet having amagnetic field strength and magnetic field polarization driven byelectrical current, and the controller positions the electromagnet at aneffective distance and an effective plane with respect to thetherapeutic target, and rotates the magnetic field of the electro-magnetby adjusting the electrical current.

The therapeutic system can further include a display for viewing themagnetic rotors and therapeutic target, and a user interface forcontrolling the magnetic rotors, such that a user can control themagnetic rotors to clear the therapeutic target at least in part byadjusting a frequency of the rotating magnetic field, a plane of therotating magnetic field with respect to the therapeutic target, and/or adistance of the rotating magnetic field with respect to the therapeutictarget. In various aspects, the therapeutic target can be a thrombosisin a human blood vessel. In various aspects, the magnetic rotors can bemagnetic nanoparticles injected into the circulatory system.

In various aspects, the obstruction to be treated using the system is athrombosis in a human blood vessel, and the magnetic rotors are formedby magnetic nanoparticles injected into the circulatory system. In thesystem, the magnetic rotors can traverse through the fluid in agenerally circular motion by repeatedly (a) walking end over end alongthe blood vessel away from the magnetic field in response to therotation of the rotors and an attractive force of the magnetic field,and (b) flowing back through the fluid towards the magnetic field inresponse to the rotation of the rotors and the attractive force of themagnetic field.

In some embodiments, a system is provided for increasing fluid flow in acirculatory system comprising a magnet having a magnetic field forcontrolling magnetic rotors in the fluid, a display for displaying, to auser, the magnetic rotors and the therapeutic target in the fluid, and acontroller, in response to instructions from the user, controlling themagnetic field to: (a) position the magnetic rotors adjacent to thetherapeutic target, (b) adjust an angular orientation of the magneticrotors with respect to the therapeutic target, and/or (c) rotate andtraverse the magnetic rotors through the fluid in a circular motion tomix the fluid and substantially clear the therapeutic target.

In various aspects, the display can display real time video of themagnetic rotors and the therapeutic target, and the display cansuperimpose a graphic representative of a rotation plane of the magneticfield and another graphic representative of the attractive force of themagnetic field on the real time video. In some aspects, the magnet canbe a permanent magnet coupled to a motor and a movable arm, and thecontroller can include a remote control device for a user to manipulatethe position, rotation plane and/or rotation frequency of the magneticfield with respect to the therapeutic target.

In some embodiments, the display can adjust the graphics in response toinstructions received from the user through the remote control device.In various aspects, the magnet can be an electromagnet coupled to amotor and a movable arm, and the controller can perform image processingto identify the location, shape, thickness and/or density of thetherapeutic target, and can automatically manipulate the movable arm tocontrol the position, rotation plane and/or rotation frequency of themagnetic field to clear the therapeutic target.

In some embodiments, the magnetic rotors are formed by magneticnanoparticles which combine in the presence of a rotating magneticfield. In some aspects, the fluid can be a mixture of blood and atherapeutic agent (e.g., a thrombolytic drug), the blood and therapeuticagent being mixed by the generally circular motion of the magneticrotors to erode and clear the therapeutic target. In some aspects, thegenerally circular motion of the magnetic rotors can redirect thetherapeutic agent from a high flow blood vessel to a low flow bloodvessel which contains the therapeutic target.

An example embodiment of a magnetomotive stator system is illustrated inFIG. 1A (isometric view) and FIG. 1B (cross-section view). The operationof components is shown for this system involving rotation about a singleaxis 132. The permanent magnet cube 102 possesses a North 104 and aSouth 106 magnetic pole. In one embodiment, the permanent magnet 102measures 3.5 inches on each side. The permanent magnet 102 may comprisea number of permanent magnet materials, including Neodymium-Boron-Ironand Samarium-Cobalt magnetic materials, and may be made much bigger orsmaller. For example, the permanent magnet 102 can be greater than orequal to 1 inch on each side and/or less than 10 inches on each sideincluding but not limited to between about 1 inch and about 5 inches,between about 2 inches and about 6 inches, between about 3 inches andabout 8 inches, between about 3 inches and about 4 inches, between about4 inches and about 10 inches, overlapping ranges thereof, less than 6inches, less than 5 inches, less than 4 inches. The shape of thepermanent magnet 102 can be a shape other than a cube, such as, forexample, a sphere, a cylinder, a rectangular solid, an ellipsoid, orsome other shape. Other configurations of the permanent magneticmaterial may improve performance in shaping the field so that aspects ofthe magnetic field and gradient are improved or optimized in terms ofstrength and direction. In some embodiments, the permanent magneticmaterial may be configured in a way to make the system more compact. Acylinder comprising permanent magnetic material is one such example.Cylindrical magnets may reduce the mass of the magnet and allow the massof the magnet to be positioned closer to the patient. However, simplerectangular and cubical geometries may be cheaper to purchase ormanufacture.

The face of the permanent magnet 102 in which the North 104 and South106 poles reside is glued, attached, bonded, affixed, welded, orotherwise fastened or coupled to a mounting plate 108. The mountingplate 108 can comprise magnetic or nonmagnetic material. Optionally,magnetic materials can be used to strengthen the magnetic field for someconfigurations of the permanent magnetic material. In some embodiments,nonmagnetic mounting plates can be desirable as they may be easier toaffix or couple to the permanent magnet 102.

This mounting plate 108 is attached to a flange 110 that passes througha first bearing 112 and a second bearing 114, both of which aresupported by the bearing mounting structure 116. Many standard bearingsare at least partially magnetic. Accordingly, in some embodiments, theflange 110 is constructed from a nonmagnetic material to ensure themagnetic field does not travel efficiently from the flange 110 into thebearings 112 and 114. If this were to happen, the bearings couldencounter more friction due to the magnetic attraction of the flange 110to the bearings 112 and 114.

The end of the flange 110 is connected to a coupling 118, which connectsto a drive motor 120. The motor 120 may be a DC motor or an AC motor. Ahigh degree of precision is capable with a servo motor. In someembodiments, a step-down gearbox may be advantageously used to spin thepermanent magnet 102 at the desired rotation frequency, given that manymotors typically spin faster than is desired for the wireless control ofmagnetic rotors as described herein.

The drive motor 120 is attached to a motor support structure 122, whichaffixes the drive motor 120 to a platform 124. Attached to the platform124 is a suspension mounting bracket 126 (located but not shown in FIG.1B), which is connected to a suspension arm 128. The suspension arm 128possesses an attachment joint 130. The suspension arm 128 may besuspended from overhead, from the side, from the bottom, or from someother location depending on a desirable placement of the magnetomotivestator system.

Operation of the Magnetomotive Stator System

The magnetomotive stator system (e.g., magnetomotive stator system 602of FIG. 7A) can be positioned by the use of a portable support base 202as shown in FIG. 2. Once in place, and as shown in FIG. 7A, a computercontrol panel 604 with a display (e.g., computer display) 606 and usercontrol buttons 608 are used to specify the orientation of the magneticrotation plane 616 at the user-defined point in space 610. In someembodiments, the display 606 is a touchscreen display. The field andgradient are manipulated in the physical space 610. The rotation plane'snormal vector 614 can be specified by the user in the global coordinatesystem 612 at the point in space 610, using the control button 608 or ahandheld controller 622. Within the magnetic rotation plane 616 is theinitial orientation of the magnetic field 618, which may be setautomatically by the computer or manually by a user or operator. Theuser can specify the direction of the magnetic field rotation 620 in themagnetic rotation plane 616.

An embodiment of a control process is illustrated in FIG. 8. One, more,or all of the steps in the control process can be automaticallyperformed by a computing device. One or more of the steps can beperformed by an operator. At block 702, a point in space forthree-dimensional control is identified. At block 704, an orientation ofthe axis of the magnetic field spin, which is perpendicular to themagnetic field, is set. This step can include the specification of therotation plane's normal vector 614. Using a right-handed coordinatesystem, the magnetic field can rotate clockwise around the normal vector614. At block 706, the initial direction of the magnetic field 618 isset. In some embodiments, a computer (e.g., the controller 604) canautomatically set the initial direction of the magnetic field 618. Atblock 708, the frequency of field rotation within the magnetic rotationplane 616 is set by the user or automatically by the computer. Thestrength of the magnetic gradient is calculated at block 710 and thestrength of the magnetic field is calculated at block 712. At block 714,control parameters are calculated for the magnetomotive system. Thecontrol parameters can determine the desired rotating magnetic field andmagnetic gradient. For a permanent magnet system, the control parameterscan correspond to the rotation speed of the drive motor(s) 120. For anelectromagnet system, the control parameters can describe the change incurrent in time. Once the control parameters are calculated, themagnetomotive stator system can be turned on at block 716 and themagnetic field and gradient are applied to a target area. If it isdesired or calculated that the magnetic rotation plane 616 should bechanged at block 718, the control process loops back to block 704.

Assuming the magnetomotive stator system of FIG. 1A is attached to theportable support base 202, the platform 124 may be oriented by the userthrough the suspension mounting brackets 126 attached to the suspensionarm 128, which is itself attached to the suspension arm attachment joint130. The suspension arm attachment joint 130 connects to an armpositioner 212 connected to the portable support base 202. Thesuspension arm attachment joint 130 allows rotation of the magnetomotivesystem about the end of the arm positioner 212. The suspension armattachment joint 130 also allows the platform base 124 to be rotated inthe plane perpendicular to that allowed by the suspension arm attachmentjoint 130. The motor 120, which is attached to the platform base 124 viathe motor support structure 122, spins at a desired frequency. Thisspinning, or rotating, motion is coupled to the mounting flange 110 viathe drive coupling 118. The first bearing 112 and the second bearing 114allow for the mounting flange 110 to rotate smoothly. These bearings areaffixed to the platform 124 via the bearing mounting structure 116. Thespinning, or rotating, flange 110 is rigidly attached to the magnetmounting plate 108, which is attached to the permanent magnet 102. Thus,the motor 120 spin is transmitted to the permanent magnet 102. Thelocation of the North magnetic pole 104 and the South magnetic pole 106at the ends of the permanent magnet 106 results in the desired magneticfield rotation plane 616. In this magnetic field rotation plane 616, themagnetic field rotates parallel to the front face of the magnet for allpoints located on the central drive axis 132.

As an example, for the manipulation of magnetic nanoparticles within thebody, the user-defined point in space 610 may be inside the head 624 forischemic stroke therapies in which magnetite nanoparticles aremanipulated to rapidly and safely destroy clots. Likewise, theuser-defined point in space 610 may be inside the leg 626 for deep-veinthrombosis therapies in which magnetite nanoparticles are manipulated torapidly and safely destroy clots.

As an example of magnetic nanoparticle manipulation in accordance withseveral embodiments, FIG. 9B illustrates a magnetic nanoparticle 802,which possesses a particle North magnetic pole 804 and a particle Southmagnetic pole 806, that is rotated by the clockwise rotatingmagnetomotive-generated magnetic field 812 relative to the particlereference coordinate system 808. The rotating magnetic field 812 causesthe magnetic nanoparticle to spin in the direction of the clockwiserotation angle 810. When a magnetic gradient 814 is applied and asurface 816 is present (e.g., a vessel wall), as illustrated in FIG. 9A,the clockwise rotating magnetomotive-generated magnetic field 812results in traction against the surface 816, resulting in translation818 parallel to the surface (e.g., to the right as shown in FIG. 9A).

In the presence of a fluid 820 contained within an enclosing region 822,as illustrated in FIG. 9C, the manipulation of the magneticnanoparticles when combined with the magnetic gradient 814 results incirculating fluid motion 824. When used to destroy vessel obstructions830 within a blood vessel 828, which contains blood 826 as illustratedin FIG. 9D, the magnetomotive-generated mixing can result in improvedmixing of a clot-busting (thrombolytic) drug within the blood 826. Theimproved mixing facilitates increased contact and interaction of thetherapeutic agent with the vessel obstructions 830 than would occur ifthe fluid was stagnant and not mixed, which advantageously allows forthe dose of the thrombolytic drug to be lowered from standard prescribeddoses which, by reducing the bleeding associated with higher doses ofthrombolytic drugs, results in a safer procedure. It also speeds thethrombolytic process. For example, the magnetic nanoparticles can bemanipulated to form a vortex, e.g. predictably circulate, in a region ofstagnant flow so that the thrombolytic drug is better mixed, resultingin a more efficient chemical interaction. Creating a vortex can alsodraw in more of the thrombolytic drug near the region of turbulent flow.

Methods are also provided for increasing fluid flow in a circulatorysystem comprising: (a) administering a therapeutically effective amountof magnetic rotors to the circulatory system of a patient in needthereof, and (b) applying a magnet to the patient, the magnet having amagnetic field and a gradient for controlling the magnetic rotors in acirculatory system, and (c) using a controller for positioning androtating the field and the gradient in a manner to agglomerate and movethe magnetic rotors with respect to a therapeutic target in thecirculatory system of the patient, wherein contact of the therapeutictarget with a pharmaceutical composition in the circulatory system isincreased and fluid flow is increased.

The pharmaceutical composition, according to some embodiments, can beattached to the magnetic rotor. In some aspects, the pharmaceuticalcomposition can be administered to the circulatory system of the patientseparate from the magnetic rotors. In various embodiments, thepharmaceutical composition is a thrombolytic drug.

In various embodiments, a therapeutic target can be a fluid obstructionsuch as atherosclerotic plaques, fibrous caps, fatty buildup, coronaryocclusions, arterial stenosis, arterial restenosis, vein thrombi,arterial thrombi, cerebral thrombi, embolism, hemorrhage and very smallvessel. In some aspects, the circulatory system is vasculature of apatient, particularly a human patient.

In certain embodiments, the magnet can be a permanent magnet coupled toa motor, and the controller can control a motor to position the magnetat an effective distance, an effective plane with respect to thetherapeutic target, and can rotate the magnet at an effective frequency.In some aspects, the magnet can be an electromagnet having a magneticfield strength and magnetic field polarization driven by electricalcurrent, and the controller can position the electromagnet at aneffective distance, an effective plane with respect to the therapeutictarget, and can rotate the magnetic field of the electro-magnet byadjusting the electrical current.

The system of the method can further include a display for viewing themagnetic rotors and therapeutic target, and a user interface forcontrolling the magnetic rotors, wherein a user controls the magneticrotors to increase contact of the therapeutic target with apharmaceutical composition in the circulatory system by adjusting afrequency of the rotating magnetic field, a plane of the rotatingmagnetic field with respect to the therapeutic target, and/or a distanceof the rotating magnetic field with respect to the therapeutic target.

In various aspects, the therapeutic target can be a thrombosis in ahuman blood vessel. In some aspects, the magnetic rotors can be magneticnanoparticles injected into the circulatory system. In particular, thetherapeutic target can be a full or partial blockage of a vein bivalve.In certain aspects, the magnetic rotors move through the fluid in thecircular motion by repeatedly (a) walking end over end along the bloodvessel away from the magnetic field in response to the rotation of therotors and an attractive force of the magnetic field, and (b) flowingback through the fluid towards the magnetic field in response to therotation of the rotors and the attractive force of the magnetic field.

In various aspects, the rotor is a magnetic nanoparticle of a diameterfrom about 20 nm to about 60 nm. In some aspects, the therapeutic targetis a vascular occlusion in the patient's head or a vascular occlusion inthe patient's leg.

In some embodiments, a method is provided for increasing drug diffusionin a circulatory system comprising (a) administering a therapeuticallyeffective amount of magnetic rotors to the circulatory system of apatient, and (b) applying a magnet to the patient, the magnet having amagnetic field and a gradient for controlling the magnetic rotors in acirculatory system, and (c) using a controller for positioning androtating the field and the gradient in a manner to agglomerate and movethe magnetic rotors with respect to a therapeutic target in thecirculatory system of the patient, wherein diffusion of a pharmaceuticalcomposition in the circulatory system at the therapeutic target isincreased.

Real-Time Control with Imaging

In some embodiments, the system provides real-time information forimproved control of the magnetic nanoparticles. The magneticnanoparticles can be configured to be detectable with an imagingmodality. For example, the magnetic nanoparticles may be attached to acontrast or nuclear agent to be visible using an x-ray-based system orPET scanner, respectively. Other imaging modalities can include nuclearmagnetic resonance spectroscopy, magnetic resonance imaging, computedtomography, and/or Doppler (e.g., transcranial Doppler) which may detectthe fluidic current created by the magnetic nanoparticles.Ultrasound-based diagnostic imaging modalities may also be used.

Combining the control system with an imaging system can advantageouslyprovide the ability to improve directed therapy. In someimplementations, the imaging system can provide information suitable fortracking the infusion of a therapeutic agent (e.g., chemical adjunct) inreal-time toward therapeutic targets (e.g., low-blood-flow lumens havingone or more partial or complete obstructions or blockages). For example,magnetic nanoparticles can be configured to act as contrast agents inapplications where magnetic nanoparticles are associated with one ormore drugs or therapeutic agents. Using magnetic nanoparticles in suchapplications allows the nanoparticles to be used as a measure of drugdiffusion. Based on imaging data, the control system can correlate aconcentration of the contrast agent with an amount of magneticnanoparticles at a location. As a result, parameters of the therapy canbe adjusted to alter diffusion of the drug or therapeutic agent (e.g.,by altering the manipulation of the magnetic nanoparticles by adjustingthe control parameters of the magnetic-based control system).

In certain embodiments, the imaging system can provide information tothe system and/or a user suitable for switching the system betweenoperational modes. For example, the imaging system can provide images tothe control system indicating the location and concentration of magneticnanoparticles within a subject. Based on this information, the system ora user can cause the magnetic system to provide magnetic fieldsconfigured to collect magnetic nanoparticles in a defined location orcause the magnetic system to provide magnetic fields configured to mixor vortex magnetic nanoparticles in a location. By manipulating themagnetic system according to received image information, the controlsystem can control the infusion of magnetic nanoparticles in response toconditions within the subject and in one, two, or three dimensions,thereby improving the ability to direct the therapy.

The imaging modality can be any imaging modality capable of resolving adevice or chemical agent which is affected by the fluidic currentgenerated by the magnetic nanoparticles. The modality could be able toimage the area of interest and provide metric information. The systemcan include a communication module for communicating imaging data to anexternal device, such as a display device and/or storage device. Thesystem can include a registration module for registering the referenceframe of the image to the reference frame of the magnetic system. Thesystem can then receive the image, register the image, track themagnetic nanoparticles, and provide a means of directing thenanoparticles to be navigated along a desired path, either by anoperator or automatically by a computer controller. The imaging data canbe two-dimensional or three-dimensional. Three-dimensional informationcould be advantageous where navigation occurs in three dimensions. Insome embodiments, the control of the magnetic nanoparticles can occurremotely using the systems described herein.

FIG. 10 illustrates a flow chart of an embodiment of a process 1000 forcontrolling magnetic nanoparticles. At block 1020, the system acceptsthe imaging data from the imaging system. Accepting the imaging data caninclude receiving the information from the imaging system. In someimplementations, the system can request an image and/or direct theimaging system to provide an image at a defined time and/or location.

At block 1025, the system registers its reference frame to that of theimaging system. The imaging system can provide information regarding theposition and orientation of the system to aid in registering thereference frames. Registering the reference frames can includeidentifying or detecting features in an image and comparing them toprevious images to properly align the reference frames.

At block 1030, the system tracks the magnetic nanoparticles. Asdescribed above, the magnetic nanoparticles can include a coating orchemical agent that makes them detectable for a given imaging modality.Using the images received from the imaging system, the control systemcan identify the location of the magnetic nanoparticles. The currentlocation of the magnetic nanoparticles can be compared to previousnanoparticles and the position of the magnetic nanoparticles can betracked over time.

At block 1035, the system plans or determines a navigation path.Planning the navigation path can be automatic and/or based oninformation received from a user. The navigation path can be based, atleast in part, on the imaging data received from the imaging system,patient characteristics, characteristics of the magnetic nanoparticles,the location of the therapeutic target, characteristics of thetherapeutic target, the injection site, or any combination of thesefactors.

At block 1040, the system navigates the magnetic nanoparticles accordingto the navigation plan by positioning the rotating magnet so that therotating magnetic field is oriented properly with respect to a directionof travel and to a therapeutic target site. As described above,positioning the rotating magnet can include automatic positioning by acomputer controller or manual positioning by an operator. The positionof the magnets and/or electromagnets can be controlled in one, two, orthree dimensions and the orientation of the magnets can be controlledalong one, two, or three axes as well. In addition, the system canchange the strength of the magnetic field and/or magnetic gradient andthe variation of the magnetic field and/or gradient, to direct themovement and behavior of the magnetic nanoparticles.

Additional Embodiments of the Magnetomotive Stator System

FIG. 3 depicts an embodiment in which the magnet is made to spin in aplane that is perpendicular to that shown in FIG. 1. Here the permanentmagnet 302, which possesses a North magnet pole 304 and a South magnetpole 306, possesses two support flanges. The first magnet flange 308passes through the first bearing 312 and the second magnet flange 310passes through the second bearing 314. The bearings are supported by amagnet support structure 316. The magnet support structure is connectedto a center shaft 318, which is supported by the support 320 for thecenter shaft. The center shaft 318 is attached to the motor mountingplate 322, to which is attached the drive motor 324. In this embodiment,the magnet drive motor sheave 326 is connected to the drive belt 328.The drive belt 328 is connected to the magnet sheave 330. The supportfor the center shaft 320 is attached to the magnet assembly supportstructure 332.

In some embodiments, the permanent magnet 302 is made to spin in theplane perpendicular to the front face so that the North magnet pole 304and South magnet pole 306 rotate in the same plane. The drive motor 324turns the motor sheave 326, which turns the drive belt 328. The drivebelt 328 then turns the magnet sheave 330, which is attached to thesecond magnet flange 310. The first magnet flange 308 and second magnetflange 310 pass through the first bearing 312 and second bearing 314,respectively. Both magnet flanges 308 and 310 are attached to thepermanent magnet 302, thus allowing the drive motor 324 to spin thepermanent magnet 302.

In FIGS. 4A and 4B, an embodiment of a permanent magnet 436 is depictedthat is capable of being rotated in any plane using a two-motor system.The magnet possesses a North magnet pole 438 and a South magnet pole440. The first motor 402 is attached to the central support 406 via thefirst motor flange 404. Attached to the first motor 402 is the firstmotor pulley 408. The first motor pulley 408 is connected to the firstaxle pulley 410 via the first motor belt 412. The first axle pulley 410is attached to the first axle 414 which passes through the first axlebearings 416. At the end of the first axle 414 is the first miter gear418. The first miter gear 418 engages the second miter gear 420. Thesecond miter gear 420 is attached to the second miter gear axle 422,which passes through the second miter gear bearings 424. The secondmiter gear bearings 424 are attached to the magnet support yoke 426. Thesecond miter gear pulley 428 is connected to the second miter gear axle422. The second miter gear axle 422 is connected to the magnet pulley430 by the magnet belt 433. The magnet pulley 430 is attached to one ofthe two magnet flanges 432. The magnet flanges 432 pass through themagnet bearings 434. A second motor 442, which is attached to thecentral support 406 by a second motor flange 444, which possesses asecond motor pulley 446. The second motor pulley 446 is connected to thesecond axle pulley 448 by the second motor belt 450. The second axlepulley 448 is connected to the second axle 452, which passes throughsecond axle bearings 454.

In this embodiment, the first motor 402 turns the first motor pulley410, which transmits the rotation of the first motor pulley 410 to thefirst axle pulley 410 via the first motor belt 412. The first axlepulley 410 turns the first axle 414, which is made free to turn usingthe first axle bearings 416. Turning the first axle 414 results in theturning of the first miter gear 418, which is connected to the firstaxle 414. The first miter gear 418 transmits the rotation to the secondmiter gear 420, which turns the second miter gear axle 422. The turningof the second miter gear axle 422 is made possible using the secondmiter gear bearings 424. The turn of the second miter gear axle 422results in the turning of the second miter gear pulley 428, which turnsthe magnet pulley 430 via the magnet belt 433. The magnet pulley 430turns the magnet flanges 432, which results in a turn of the magnet 436around a first axis 437.

The second motor 442 turns the second motor pulley 446, which turns thesecond axle pulley 448 via the second motor belt 450. The turning of thesecond axle pulley 448 results in the turning of the second axle 452,which is made free to rotate using the second axle bearings 454, thusallowing the magnet 436 to be rotated around a second axis 456.

FIG. 5 is an embodiment of a magnetomotive system comprisingelectromagnetic coils 502. The electromagnetic coils 502 are attached toa support structure 504. Electromagnetic coils 502 can be connected topower supplies 506 via power supply cables 508 and power supply returncables 510. The support structure is connected to a two-segment armpositioner 512. In the illustrated embodiment, power supplies 506deliver power to electromagnetic coils 502 via the power supply cables508 and the power supply return cables 510. The two-segment armpositioner 512 allows the support structure 504 to be positioned inspace. In some embodiments, the power supplies 506 control the amount ofelectric current that is generated within the electromagnetic coils 502.

Robotic Arm

In some embodiments, an arm positioner (e.g., arm positioner 212 and thetwo-segment arm positioner 512) can couple the magnet system to a base(e.g., portable base 202). The arm positioner can be a robotic armcapable of positioning and orienting the magnetomotive system withoutbeing constrained by movement along one or two axes. The arm positionercan provide universal movement. The arm positioner can include motors orother mechanical actuators that allow the arm to be controlled by anelectrical system or by a remote control. For example, the mechanicalcontrol system can allow an operator to control the position of themagnetic system in one, two, or three dimensions through a remotecontrol, computer, electrical controls, or the like. In this way, theoperator can manipulate the position and orientation of the magnet(s) inaddition to manipulating the strength and/or variation of the magneticfield. In some embodiments, the arm positioner can be used inconjunction with the magnetomotive systems depicted in FIGS. 1, 3, and4. In some embodiments, the position of the magnets is controlledthrough other electrical means in addition to or as an alternative tothe arm positioner, such as with cables, rails, motors, arms, or anycombination of these. In some embodiments, the position and orientationof the magnets is controlled at least in part through a five-axisrobotic arm. In some embodiments, the arm positioner provides movementwith six degrees of freedom. In certain embodiments, the electricalcontrol of the position of the magnets can be included in a systemhaving a display coupled to an imaging modality and computer controlsuch that the operator can control the infusion and navigation ofmagnetic nanoparticles in real-time in response to the display andimaging of the patient.

In some embodiments, the robotic arm can be automatically manipulated bythe magnetomotive system. Automatic manipulation allows themagnetomotive system to stow the magnetic system in a substantiallyshielded enclosure, thereby substantially reducing or preventingmagnetic fields of one or more magnets of the system from having aneffect on persons or items outside the system. For example, the systemcan include an enclosure made out of a suitable shielding material(e.g., iron). The automatic manipulation provided by the controller canmove the one or more magnets of the system into the shielded enclosurewhen not in use.

Portable Magnet Pod with Rail Attachment

FIG. 6 illustrates a schematic drawing of an embodiment of a portablemagnet pod 650 with a rail attachment 652. The portable magnet pod 650can be designed to be carried by and secured (detachably or fixedly) toa patient bed or transport device, for example, in a hospital, urgentcare facility, at home, in an ambulance, in a helicopter, or in anotheremergency vehicle. The portable magnet pod 650 can be used to controlmagnetic rotors within the patient in a manner similar to that describedherein with reference to the various magnetomotive and magnetic systems.

In some embodiments, a portable magnet pod 650 includes a magnet pod 654configured to house permanent magnets and/or electromagnets, and theassociated electrical and/or mechanical support and control elements forcreating a desired magnetic field. The electrical and/or mechanicalcomponents can be similar to those described herein with reference tothe various magnetomotive stator systems. The portable magnet pod 650can include controls 660 configured to operate the portable magnet pod650, for example, allowing an operator to manipulate a desired magneticfield to control magnetic nanoparticles injected into a patient.

The portable magnet pod 650 can include a rail attachment 652 attached(detachably or fixedly) to the magnet pod 654 to provide stability. Insome embodiments, the rail attachment 652 eliminates a need to forsetting of the patient's supine, or head elevation, angle. The railattachment 652 can substantially secure the pod to the rail of a bed,gurney, stretcher or other patient transport device. In situations wherethe portable magnet pod is used for a patient suffering a stroke or hasa clot or obstruction in a blood vessel leading to the brain, theattachment of the portable magnet pod 650 to a rail can ensure that themagnetomotive system is properly aligned with the central axis of thehead and properly positioned aside the affected hemisphere of the brain.The portable magnet pod 650 can include a handle 662 configured to allowa user to conveniently carry the portable magnet pod 650 to a desiredlocation.

The portable magnet pod 650 can include an integral folding headrest 656attached (e.g., pivotably) to the magnet pod 654. The headrest 656 canbe pivoted open when being used on a patient (represented by line 658).In the open position, the headrest can aid the operator in properlyaligning the patient and the magnet(s). This can simplify the operationand/or control of a magnetic control system by ensuring that thepatient's head is at a defined distance and attitude with respect to therotating magnet(s). The headrest can be closed for convenience and easewhile transporting the system. In some embodiments, the portablemagnetic pod includes a dispensable cover for hygienic purposes.

Magnetic Tool Rotors

In some embodiments, a therapeutic system is provided for increasingfluid flow in a circulatory system comprising a magnet having a magneticfield for controlling a magnetic tool in the fluid, and a controllerpositioning and/or rotating the magnetic field with respect to thetherapeutic target to rotate an abrasive surface of the magnetic tooland maneuver the rotating abrasive surface to contact and increase fluidflow through or around the therapeutic target. In various aspects, thecirculatory system can be vasculature of a patient, particularly a humanpatient. In various aspects, the magnetic tool can be coupled to astabilizing rod, wherein the magnetic tool rotates about the stabilizingrod in response to the rotating magnetic field. In some aspects, themagnetic tool can include an abrasive cap affixed to a magnet whichengages and cuts through the therapeutic target. In certain aspects, thecontroller positions the magnetic tool at a target point on thetherapeutic target, and rotates the magnetic tool at a frequencysufficient to cut through the therapeutic target. In some aspects, themagnet can be positioned so that poles of the magnet periodicallyattract the opposing poles of the magnetic tool during rotation, and themagnetic tool is pushed towards the therapeutic target by a stabilizingrod upon which the magnetic tool rotates. In some aspects, the magnetcan be positioned so that the poles of the magnet continuously attractthe opposing poles of the magnetic tool during rotation, and themagnetic tool is pulled towards the therapeutic target by an attractiveforce of the magnet.

FIG. 11 shows an example use of the magnetomotive stator system towirelessly manipulate a mechanical thrombectomy device (also referred toas a “magnetic tool” above). In this example, a vessel obstruction 830inside a blood vessel 828 is unblocked by a rotating magnet 902 whichpossesses a North magnet pole 904 and a South magnet pole 906 indirections transverse to the axis 908. The magnet 902 follows theexternal magnetic field vector 812, which is generated wirelessly by themagnetomotive stator system. The external magnetic field vector 812changes in time in the direction of the magnetic field rotation angle810. The rotation of the magnet 902 is stabilized by passing astabilizing rod 908 through a hole in the magnet 902. The magnet 902 isfree to rotate about the stabilizing rod 908. An abrasive cap 910 isaffixed to the magnet 902 which engages the vessel obstruction 830. Thisabrasive cap 910 may use a coating or surface treatment that ensuresminimal damage to healthy tissue and maximal damage to the vesselobstruction 830.

In accordance with several embodiments, the use of the magneticgradient, which may be time-varying, and a time-varying magnetic fieldallows for devices to be constructed which possess a magnet capable ofrotating at the distal end. The magnetomotive devices described hereincan be made much smaller and cheaper than existing clinical devices usedto amplify the effects of pharmaceuticals or to bore throughobstructions in the vasculature. Moreover, commercial technologies thatuse a rotation mechanism within a vessel or chamber require a mechanicalor electrical transmission system from the proximal end to the distalend, which can complicate the device, make the device more expensive,and/or increase the overall size. Systems and devices described hereincan generate mechanical action wirelessly at the tip without the needfor a mechanical or electrical transmission system, thereby allowing thedevice to be smaller, simpler, and/or cheaper to manufacture.

For example, the magnetic-based system may be used in a clinical settingfor the enhancement of the effectiveness of tPA which is injectedintravenously. Magnetic particles (e.g., magnetic nanoparticles) can beinjected either before or after introduction of the tPA within thevasculature, or can be attached to a thrombolytic agent (e.g., tPA). Themagnetic-based system, which is placed or positioned close to thepatient (e.g., within two feet, within 1 foot, within 10 inches, within9 inches, within 8 inches, within 7 inches, within 6 inches, within 4inches, within 3 inches, within 2 inches, within an inch of the patient)and near a location of a therapeutic target (e.g., an obstruction, aclot), can be activated. In some embodiments, the magnetic-based systemwould not need to be generating a changing (e.g., rotating) magneticfield at this time in that the gradient would be sufficient to collectparticles at the therapeutic target (e.g., an obstruction, a clot). Whenmagnetic-based mixing of fluid within the vasculature is desired, themagnetic field can be made to alternate in time (e.g., by rotating oneor more permanent magnets or controlling current through coils of anelectromagnet) which, when combined with the magnetic gradient, whichmay or may not be varying in time, causes the action of the therapeuticagent (e.g., a thrombolytic agent such as tPA) to be enhanced. Inaccordance with several embodiments, a clot or other fluid obstructionor blockage could be destroyed faster and better as compared to existingapproaches. For example, the magnetic nanoparticles can be manipulatedto form a vortex (e.g., predictably circulate) in a region of stagnantflow so that the therapeutic agent (e.g., tPA) is better mixed,resulting in a more efficient drug interaction. Creating a vortex canalso draw in more of the therapeutic agent near the region of turbulentflow.

FIGS. 12A and 12B illustrate an example method of use of a magnetomotivestator system (e.g., FIG. 4) and magnetic nanoparticles for thetreatment of a vascular occlusion in the brain 1004, in accordance withan embodiment of the invention. FIG. 12B shows a drip bag 1006 and aninjection needle 1008 coupled to a conduit or tubing inserted at aninjection location 1010 of an arm 1012 of a patient. FIG. 12A is aclose-up schematic illustration of a portion of the vasculature of thebrain 1004 including a blood vessel 828 where blood flow 1002 isunobstructed and a vessel branch having an obstruction 830. FIG. 12Aalso illustrates a rotating magnetic nanoparticle (e.g., FIG. 9B) nearthe obstruction 830.

Magnetically-Enhanced Drug Diffusion

FIG. 13 illustrates some examples of how to magnetically enable controlover the diffusion of a therapeutic agent (e.g., a chemical or adjunct)injected into a moving fluidic system (e.g., circulatory system). In theillustrated model, fluid A is travelling and permeates the fluidicsystem (illustrated as the white region in FIG. 13A). At a later time,fluid B is injected (illustrated as the shaded region). FIG. 13Billustrates a problem associated with solely injecting fluid B withoutintroducing and manipulating magnetic nanoparticles—fluid B is limitedin its ability to penetrate the “leg” or branch to reach a therapeutictarget because the velocity of the flow does not travel far into the legor branch. Existing systems then must rely on diffusion to dilutefluid-A with fluid-B. This can take a very long time.

In some embodiments, it has been observed that when magneticnanoparticles are placed into fluid B, and a magnetic field and gradientare applied (e.g., imposed) to pull some of the nanoparticles out of thebloodstream into the leg or branch, the nanoparticles take a bit (e.g.,an amount) of fluid B with them (as shown in FIG. 13C). Time-varyingaspects can be changed or varied to amplify the diffusion-facilitatingaction. For example, the rate of magnetic field rotation, the strengthof the magnetic gradient, the orientation of the source field, the sizeand strength of the magnetic nanoparticle, or any combination of thesecan be changed to amplify the action. In time, more nanoparticles cancollect at the bottom of the leg or branch and begin to set upcirculation patterns (e.g., vortexing patterns), which distribute fluidB into fluid A faster than via diffusion alone. The longer the processruns, the more nanoparticles are collected, and the stronger the mixingeffect becomes, until fluid A is substantially replaced with fluid B atthe region of the therapeutic target.

In the case of clot destruction, the leg or branch represents a blocked(e.g., partially or completely obstructed or occluded) vein or artery.As depicted in FIG. 13, to facilitate contact of a therapeutic agent(e.g., thrombolytic drug) with the therapeutic target (e.g., surface ofa blocked vessel), the force of diffusion is principally involved if theobstruction is sufficiently far from the main flow. Therefore,therapeutic agents (e.g., thrombolytic drugs, chemicals, adjuncts,pharmaceutical compositions) effective in substantially clearing a fluidblockage from a circulatory system are limited in their effectiveness;relying on diffusion alone in vivo could result in negative clinicaloutcomes. Because therapeutic agents (e.g., thrombolytic drugs,chemicals, adjuncts, pharmaceutical compositions) effective insubstantially clearing fluid blockages from a circulatory system mayhave a relatively short half-life, the use of the magnetomotive statorsystems, in combination with the magnetic nanoparticles describedherein, can speed the process of clearing fluid blockages by thetherapeutic agents. If the objective is to deliver a therapeuticconcentration of fluid B at the end of the leg or branch which is afraction of the concentration in the main flow, use of the systems andmethods described herein can result in the same therapeuticconcentration of fluid B for a much smaller dose of fluid B initiallyinjected (See FIG. 38). Thus, some embodiments provide enhancedtherapeutic advantages by allowing the use of a smaller dose of atherapeutic agent than would normally be used without the introductionof magnetic nanoparticles controlled by the magnetic-based controlsystems described herein, thereby reducing the occurrence of bleeding oreven death due to excessive doses. For example, the dose of therapeuticagent used on conjunction with the magnetic nanoparticles andmagnetic-based control systems described herein can be less than orequal to about 50%, about 45%, about 40%, about 35%, about 30%, about25%, about 20%, about 15%, about 10%, about 5%, of the standardprescribed dose.

For example, systems and methods described herein can be used in acollection mode to manipulate a collection of magnetic nanoparticles totranslate a stream of the magnetic nanoparticles into an occludedbranch. As a result, a fluidic current can originate from the parentvessel flow's turbulent region near bifurcation. This flow can draw in atherapeutic agent (e.g., a chemical adjunct) within the bloodstreamtowards the terminal end of the occluded branch better than by diffusionalone.

As another example, magnetic-based systems and control methods describedherein can be used in a vortexing mode to manipulate the magneticnanoparticles to create a vortex in a region of stagnant flow so that atherapeutic agent (e.g., chemical adjunct) is better mixed within thebloodstream, resulting in a more efficient chemical reaction with afluid obstruction (e.g., due to continuous refreshing of the portions ormolecules of the therapeutic agent that is in contact with the fluidobstruction). In some embodiments, clot dissolution time can beincreased by a factor of three or more when the vortexing mode is used.Such manipulation can be achieved by oscillating a magnetic field indifferent directions at a particular frequency. For example, thefrequency can be greater than or equal to about 0.25 Hz and/or less thanabout 3 Hz, including but not limited to between about 0.25 Hz and about1 Hz, between about 0.5 Hz and about 2 Hz, between about 1 Hz and about3 Hz, between about 0.75 Hz and about 2.5 Hz, overlapping rangesthereof, less than 3 Hz, less than 2 Hz, less than 1 Hz. The vortexingmode of control can enable more of the therapeutic agent (e.g., chemicaladjunct) to be drawn in near the region of turbulent flow.

In accordance with several embodiments, alternating between thecollection and vortexing modes can result in an improved ability to drawthe therapeutic agent (e.g., chemical adjunct) near a region ofturbulent flow and translate that therapeutic agent in a better way intoan occluded branch. Alternating between the collection mode and thevortexing mode can include altering the magnetic gradient and/or thetime-varying magnetic field to cause the magnetic nanoparticles tobehave differently. For example, in the collection mode, the magneticgradient can be increased and the time-varying magnetic field can bedecreased such that the magnetic nanoparticles experience a net forcethat results in the magnetic nanoparticles substantially accumulating ata desired location. As another example, in the vortexing mode, themagnetic gradient and/or the time-varying magnetic field can be adjustedsuch that the magnetic nanoparticles experience a time-varying net forcethat results in circulating motion and/or angular velocity within adesired region. Thus, by changing the magnetic field properties (e.g.the magnetic gradient, the magnetic field strength, orientation of themagnetic field, direction of the magnetic field, etc.) as a function oftime, the magnetic-based systems and control methods can be used in andswitched between collection mode, vortexing mode, navigation mode, orsome combination of modes.

In the case of the magnetic tool, the system is capable ofadvantageously grinding away large volumes of thrombus or other blockagematerial, such as atherosclerotic plaque material, quickly and veryprecisely. It has been observed that, in accordance with someembodiments, a 2 French hole (⅔ mm) was cut through a mockatherosclerotic clot using an embodiment of the wireless magnetomotivestator system. With respect to the use of magnetic nanoparticles, thesystem allows for more precise control of magnetic nanoparticles tocreate a relatively “gentle” scouring action that allows the leaf valvesin the veins to remain intact and undamaged. With respect to themagnetic tool, this action can be used in combination with thrombolyticdrugs to remove clot material in an occluded artery or vein. When usedwith a thrombolytic drug to treat a blood clot, the thrombolytic drugcould be helpful when mechanical action is intended to be minimized.Using magnetic nanoparticles, the material removed from the blocked veincan be captured with a small magnet on a guide wire. Depending on themode of operation, the removed material has been observed to be small(less than 1 mm size clot particles), or ball mixtures of clot material,drug and magnetic nanoparticles. Both the magnetic nanoparticlecollection and magnetic tool objects are capable of being visualizedwith standard imaging technologies allowing for computer-reconstructedpath planning.

Furthermore, imaging technologies can be incorporated into (e.g.,communicatively coupled to) the magnetic control system such that anoperator can have real-time feedback of the position of the magneticnanoparticles, thereby allowing for dynamic control and navigation. Thereal-time feedback provided by imaging technologies can increase theeffectiveness of the process, for example, by providing adjustment ofparameters of the rotating magnetic field (e.g., orientation, position,rotation frequency) and/or the magnetic gradient, by introducing morenanoparticles and/or by introducing increased quantities of therapeuticagents.

The real-time feedback can include information related to theconcentration of therapeutic agent in a particular location (e.g.,adjacent a fluid obstruction of an obstructed blood vessel), informationrelated to the concentration of magnetic nanoparticles or nanorods in aparticular location (e.g., adjacent a fluid obstruction of an obstructedblood vessel), which may be correlated to or indicative of theconcentration of therapeutic agent at the location, images of the fluidobstruction, information related to fluid flow through an obstructedblood vessel, and/or other information. The information received throughthe imaging technologies can be used to determine when to switch betweenthe collection and vortexing modes, which can be performed manually byan operator or automatically by a computer controller. For example, ifit is determined that a concentration of therapeutic agent or magneticnanoparticles or nanoparticle rods is low at a location adjacent atherapeutic target, the magnetic control system can be switched to orremain in the collection mode to increase the concentration levels. Ifit is determined that a concentration of therapeutic agent or magneticnanoparticles or nanoparticle rods is sufficient, the magnetic controlsystem can be switched to or remain in the vortexing mode.

FIG. 14 illustrates an embodiment of a magnetic field generator. In thedepicted figure, the generator 1200 comprises a permanent magnet source1205 with North 1206 and South 1207 poles, mounted so that two separaterotations about axis 1210 and about axis 1215, respectively, areenabled. For spin about axis 1210, magnet source 1205 is rotated bypulley belt 1225, which is driven by geared shaft 1226, which in turn isdriven by driving gear 1230. Gear 1230 is mounted on thrust bearing 1235and driven by motor 1240 mounted on rotor system 1225, 1226, 1230 thatenables rotation about the spin axis 1210 using a motor 1245. A separatedrive system enables rotation about second axis 1215 using components1220, thrust bearing 1235, and motor 1240. The generator is positionedwith the jointed arm 1250.

In some embodiments, the jointed arm 1250 is a robotic arm, configuredto move translate the generator 1200 in one, two, or three dimensionsand/or rotate the generator along one, two, or three axes. The jointedarm 1250 can include one or more joints to facilitate positioning andtranslation of the generator 1200. In some embodiments, the jointed arm1250 allows for unrestricted free motion that is not dependent onmovement along or about fixed axes. The jointed arm 1250 can beconfigured to move automatically and/or through operator remote control.The generator 1200 advantageously provides simplicity, smaller size, andlower cost in accordance with several embodiments.

In some embodiments, the generator 1200 has additional features wherethe simplicity of the design of generator 1200 is not desired. Thegenerator 1300 depicted in FIG. 15 displays an example of such anembodiment. FIG. 15 is a schematic drawing of an embodiment of a fieldand gradient generating device. FIG. 15 is a block diagram of a magneticfield generator 1300 surrounding a human leg 1360 having a blood vessel1355 with an obstruction 1350. Three coils, 1301, 1302, and 1303, arefed currents from drivers 1311, 1312, and 1313, through connections1321, 1322, and 1323, respectively. Drivers 1311, 1312, and 1313 arecurrent sources controlled separately by a distributing circuit 1330,which receives information from a computing device 1335. Currentsources, 1311, 1312, 1313, can be capable of generating a sine wavecurrent sufficient to provide the peak magnetic field desired. In someembodiments, the peak magnetic field is less than or equal to about 0.3Tesla. If different magnetic field characteristics are desired inindividual cases, the currents may have more complex temporal variationsthan sine waves. As determined by computing device 1335, in response tooperator input 1341, the distribution and types of currents and theirsequences to the coils can be calculated by the computing device 1335.The specific operational instructions from programs stored in memorycommunicatively coupled to the computer 1335 are based on knowledge ofthe particular operation, with specific instructions thereby providedfor operating according to the procedure input by the operator (e.g.,physician). The generator 1300 advantageously provides added flexibilityin the type of fields generated from the more complex magnetic fieldsources and the computer input, and the added refinement to the newprocedures.

Two major classes of blockage in the medical cases to be treated bymethods described herein are partial and total. Partial blockage yields,in general, low blood flow, while total blockage will result in no bloodflow. In both cases, the effectiveness of a drug delivered to remove theclot by conventional means will generally be difficult and inefficient.The delivery of the drug to the surface of a clot is in principledifficult and inefficient in spite of special methods to stir thedrug-blood mixture near a clot. Major limits to methods of removing theblockages include the difficulty of effective drug action on anocclusion, the incompleteness of removal of dislodged material, damageto vessels and adverse effects of downstream components of the removedmaterial. FIGS. 16A and 16B exhibit the underlying physical reasons forthe difficulty and inefficiency of conventional treatments of a bloodclot, and for which this disclosure provides major improvement.

FIG. 16A is a cross sectional view of a typical accumulation ofoccluding material in a bend of a section of a blood vessel 1400 havingno flow, illustrating a common difficulty in using a drug (e.g.,thrombolytic drug) for dissolving the occluding material. Adjacent avessel wall 1405 is a target region of deposited occluding material1410, the “clot,” with internal boundary edge 1415. In the depictedexample, the physician or other medical professional has introduced adrug 1425 in the vicinity of the clot. FIG. 16A exhibits the typicalsituation of a stagnant action layer 1430 of partially interactingmaterial and a layer 1435 of more concentrated but less effective drug.Layers 1430 and 1435 separate the clot from the more concentratedthrombolytic drug 1425 that had been injected into the vessel 1400 inthe general region of the target region. Motion and distribution of thedrug can arise from thermal agitation and slow dispersion as a means ofrefreshing contact between the clot and the injected drug, which makesthe action extremely slow and inefficient. Some practitioners haveintroduced metal stirrers, venturi flow-based jets, and sound-basedagitation technologies to increase efficiency, but the difficulties andlimitations of those methods have been documented.

FIG. 16B is a cross section view of a target occlusion 1455 formedagainst a wall 1460 of a vessel 1465 having a stiffened valve leaflet1470, with low blood flow in a region 1480 and with relatively low fluid(mixed blood and drug) flow at the clot surface 1457. As a result, thereis relatively little interaction between the clot and a drug 1475injected upstream into the region 1480. One approach could be toincrease the quantity of drug 1475 injected upstream, but this may beundesirable due to potential adverse effects caused by increased drugdose and/or cost. Other typical approaches involve closing off thevessel and slowly injecting a thrombolytic agent, with slow, inefficientdissolving of the clot, and the injection of large quantities ofthrombolytic drug, thus exhibiting approximately the same difficultiesof the case with a blocked vessel (e.g., vein). Some treatments provideartificial mechanical, venturi flow-based, and sound-based agitation inregion 1480 in attempts to enhance the efficiency of interaction at theclot surface 1485. Catheters with jets may spray thrombolytic drugs inattempts to get more efficient dissolution of the clot. Removal of theoccluding material is sometimes performed by insertion of mechanicaldevices, with considerable difficulty and with danger to the valve. Allof these methods may be helpful in some cases, but are generally oflimited effectiveness.

FIGS. 17A through 17C exhibit the underlying process, according to someembodiments, in the development of nanoparticle rods from chains ofmagnetic nanoparticles. FIGS. 17A-17C show a cross section of thesequence of structuring of coated or uncoated magnetic nanoparticleswith increasing magnetic field. Increase of the field during a risingpart of the cycle may cause more and more nanoparticles to align intolonger nanoparticle rods.

These are shown with zero field in FIG. 17A as nanoparticles in a randomdisposition of particles 1505, arrayed so as to be roughly evenlydistributed in space, and having a certain statistical fluctuation inposition. In FIG. 17B, when a small external magnetic field 1510 isapplied to the same group of nanoparticles, they are formed into a loosearray 1515 of short, oriented magnetic “rods.” At a certain larger field1520, depending on nanoparticle size and coating, shown in FIG. 17C, thesame nanoparticles aligned as magnetic rods 1525 have become longer. Inthis figure, it is depicted that the rods are uniform in size althoughthat is not strictly the case, nor is it necessary. This magneticprocess can be viewed in two ways: a) the field increase from FIG. 17Ato FIG. 17B being that in a single (slow) cycle of magnetic fieldalternation, or b) the increase over a number of cycles as thepeak-to-peak magnitude of the field generated is increased. Depending onthe absolute scale and oscillating frequency, the actions are notreversed during a given cycle of oscillation. In general, the methodapplies magnetic fields of greater than or equal to about 0.01 Teslaand/or less than or equal to about 1 Tesla, including but not limited tofrom about 0.01 Tesla to about 0.1 Tesla, from about 0.05 Tesla to about0.5 Tesla, from about 0.1 Tesla to about 0.6 Tesla, from about 0.3 Teslato about 0.9 Tesla, from about 0.5 Tesla to about 1 Tesla, overlappingranges thereof, less than 1 Tesla, less than 0.5 Tesla, less than 0.25Tesla, less than 0.1 Tesla. Gradient strength can be greater than orequal to 0.01 Tesla/m and/or less than or equal to 10 Tesla/m, includingbut not limited to from about 0.01 Tesla/m to about 1 Tesla/m, fromabout 0.01 Tesla/m to about 3 Tesla/m, from about 0.05 Tesla/m to about5 Tesla/m, from about 1 Tesla/m to about 4 Tesla/m, overlapping rangesthereof, less than 5 Tesla/m, less than 3 Tesla/m, less than 2 Tesla/m,less than 1 Tesla/m. In general, rods can have a length that is greaterthan or equal to about 0.05 mm and/or less than or equal to about 3 mmin length, including but not limited to from about 0.05 mm to about 2mm, from about 0.1 mm to about 2 mm, from about 0.2 mm to about 1.5 mm,from about 0.2 mm to about 1 mm, from about 0.3 mm to about 0.9 mm, fromabout 0.4 mm to about 0.8 mm, overlapping ranges thereof, less than 3mm, less than 2 mm, less than 1.5 mm, less than 1 mm.

At a certain rotating magnetic field strength and field rotationfrequency, depending on nanoparticle size and coating, the rods willreach a saturation field and achieve a maximum length, developing asdepicted in the graph of FIG. 18. The rod growth is not necessarilyexact, and the curve illustrates a general nature of the growth. Fullydeveloped rods may contain a number of nanoparticles, as many as 10 ormany more, depending on their size, and the magnitude of the rotatingmagnetic field. The rods are not stiff, depending on the magnetic fieldand gradient, and on the amount of magnetite in each nanoparticle aswell as the nanoparticle size. Other materials may be attached tonanoparticles for chemical, magnetic, and imaging reasons. That chemicalcan be a thrombolytic drug. The thrombolytic drug can also be injectedindependently.

FIG. 19 illustrates geometric features of the end-over-end walk of asingle rotating rod acting from application of a rotating magnetic fieldemanating from a fixed source in space. It displays a sequence of 8positions of a single rotating rod as it rotates and walks, so as toexhibit the directions of field and pulling force of the gradient. It isto be understood that the effective magnetic moments of individualnanoparticles are substantially continually aligned with the localmagnetic field, so that they maintain the interactions to retain the rodand its magnetic moment, while the field and rod are rotating, that is,maintaining alignment of the rod with the field.

Without being bound by a particular theory, and as will be discussed inthe following section in equations [1] and [2], the field B establishesa torque, but it does not exert a pulling force on the rod moment, whilethe gradient G exerts a pulling force but no turning torque on themoment. Therefore, a rotating magnet source will have a pulling gradienttowards it, shown as the downward arrows in stages shown in FIG. 19.Smaller magnetic nanoparticles (generally below 200 nm, below about 170nm, below about 150 nm in diameter) act primarily as magneticallypermeable materials, which substantially align with the local fieldwithout individually rotating in space. In FIG. 19, trigonometriclabeling illustrates the geometrical (angular) aspects of changingcomponents of the force and torques on the nanoparticles as related tothe walk of the rod towards the right in response to the rotating field.In other words, the rods act approximately as fixed magnetic rods. InFIG. 19, the field direction in each of the 8 positions, is shown byarrows 1701, 1711, 1721, 1731, 1741, 1751, 1761, 1771 as the fieldrotates clockwise. The rod magnetic moments 1702, 1712, 1722, 1732,1742, 1752, 1762, 1772 follow that direction. In the stages shown inFIG. 19, however, the arrows 1703, 1713, 1723, 1733, 1743, 1753, 1763,1773 point downward towards the center of the rotating field source,representing the magnetic gradient according to equation [2] below. Onthe scale of the rod lengths, about 2 mm, the movement to the right issmall relative to the distance to the source magnet.

FIGS. 20A and 20B illustrate the development of a limit to theconcentration of magnetic rods when the source magnetic field isrotating about a fixed position of the source magnet. The gradient,unlike the field, may pull towards the magnetic center of the source.The field B itself creates a torque τ of alignment on a magnetic dipolemoment μ:τ=μB sin φ,  [1]

where φ is the angle between the direction of the magnetic moment μ andthe magnetic field B. A uniform field without gradient will not create anet force on the moment μ. However, a gradient G will create a force Fon magnetic moment μ according to:F=μG cos φ,  [2]

where μ is the angle between the direction of the moment μ and of thegradient G.

FIG. 20A shows the nature of the spatial “resolution” of the system inan open location for the rods. For a fixed location of the rotatingmagnet source, the pull towards it from the gradient will changedirection as the rods 1805, 1806 and 1807 walk to the right. They willhave increased their distance from the source, resulting in a loss ofstrength of the field. In FIG. 20A, as the rotating external fieldsource will have remained at the left shown by arrow 1810, the rodlocations have moved to the right of the fixed rotating magnet (belowand off screen in FIG. 20A). At the stage shown here, the arrowsdepicting the three rods 1805, 1806, and 1807 have moved far to theright from the center of the rotating source magnet system. Relative totheir size and their distance to the magnet source, this distance to theright has increased so that the field source and gradient are at anangle and are reduced in magnitude. The gradient, in the direction shownby large arrow 1810, pulls on the nanoparticles and rods, which aredriven by the traction provided according to the force of equation [2]at their locations. The gradient G can fall off with distance from thesource, typically by a factor between the inverse cube and inversefourth power of distance, while the field B is falling off with distancefrom the source roughly as the inverse cube of distance from the sourcecenter. In this walking, the force caused by the magnetic gradient isreducing which is used to pull them down onto a walking surface. As aresult, they can ultimately lose traction. For a fixed location of themagnet source, the distribution of particles begins to approximate aGaussian distribution. This distribution of particles can be used todescribe the spatial resolution of the system.

The resulting motion of the magnetic nanoparticles in the presence ofthe gradient G can be more easily described if the gradient G isrepresented as a vector having a component pointing perpendicular to thedirection of walking motion (e.g. down in FIG. 20) and a componentpointing parallel to the direction of walking motion (e.g. left in FIG.20). Once the magnetic nanoparticles travel a sufficient distance alonga surface such that the perpendicular component of the magnetic gradientG no longer provides sufficient force to maintain traction against thesurface, the magnetic nanoparticles can lose traction and changedirection. In some embodiments, the change in direction occurs due tothe parallel component of the gradient G, which acts to provide a forceon the magnetic nanoparticles opposite the walking direction and towardsthe magnetic source. As illustrated in FIG. 20A, the gradient 1810 wouldcause a force to the left on the magnetic nanoparticles which wouldresult in motion to the left because the magnetic nanoparticles nolonger have sufficient traction against the surface to walk to theright. In some embodiments, the change in direction occurs when themagnetic nanoparticles no longer have sufficient traction against thesurface to walk along said surface as illustrated in FIG. 19, and afluid flow in the region causes the magnetic nanoparticles to move in anopposite direction. In some embodiments, the change in direction iscaused by both the magnetic gradient and the flow in the region. Oncethe nanoparticles have traveled a sufficient distance in the oppositedirection, and if the magnetic gradient G is of a sufficient magnitudeand direction, then the magnetic nanoparticles can again gain tractionagainst the surface and walk along the surface in the original direction(e.g. to the right in FIG. 20A). Repeating this sequence can cause themagnetic nanoparticles to move in a circulating, or vortexing, motion.

FIG. 20B illustrates the distribution of particles that can occur whenthe angle of the gradient is changed from left to right, as a result ofthe mechanism described in FIG. 20A. This graph is for a fixed locationof the magnet source, and is useful in describing the “resolution” ofthe walking rod system. In practice, the source can be moved if desiredfor a long occlusion, depending on the medical strategy for treating it.

A consequence of the action described in FIG. 20A is that, for a fixedlocation of the rotating magnet source, the reduction in force withdistance as the rods walk can result in a distribution of rod activityapproximately as shown in FIG. 20B where the arrow 1810 simply points toa region of maximum density at closest location to a magnet, andrepresents the position dependence of the rod walking, which is ofmaximum strength when the rods are closest to the magnetic source.

The magnetic mechanics of a single rotating rod provide the “soft brush”quantities according to the following calculations. It is to beunderstood that these conditions apply directly for rod bundles thathave relatively sparsely attached clot material. Discussed below is auseful mode of operating rods in a rotating field in which the clotmaterial is allowed to become bundled with the rods, leading to softclumps that are stable and magnetically removable. Such a mode may notfollow the calculations of this section. Nevertheless, the calculationsof this section show the underlying behavior of the rotating scouringrods when lightly loaded, and a mode that may be used in cases of smallocclusion material, or cases where the delicacy of the procedure or sizeof vein or artery may not allow clumps of material to be endured. Suchcases may arise in some occlusions in the brain.

Here, for simplicity, the rods are treated as rigid. FIG. 21A is adiagram exhibiting trigonometric detail of the creation of rotationalforce and energy on the rotating rods that in turn creates turbulence toenhance drug mixing and interaction with the surface of the clot. Theelements of the action of the magnetic rotating field B are shown at agiven moment on a single rod of magnetic moment μ in a plane defined bydirections of the rod magnetic moment, and the direction of the field Bat an instant when B is directed at an angle) β from the x-axis. At thisinstant the (constant) moment μ is directed at an angle θ from thex-axis. Therefore, at this instant the magnitude of the torque τgenerated on the moment μ by the external source magnet is given by:τ=μB sin(β−θ),  [3]

FIG. 21B shows, in coordinates centered at the center of a symmetricalrod, the angular force F(θ) exerted on the rod, which is assumed to besymmetrical. This assumption is practical when the rod size is smallcompared with the distance to the magnet source. The resulting force:F _(θ)=2μ(B/L)sin(β−θ)  [4]

is generated by the field B at the ends of a rod of length L.

A drag force might be approximated from standard mechanics with angularvelocity dependence (dθ/dt)², that is:F _(drag) =−C(dθ/dt)²  [5]

where C is a proportional constant. Under that assumption, the finalequation of motion for a symmetric rod is:(mL/4)(d ² θ/dt ²)=2μB/L[sin(β−θ)]−C(dθ/dt)²  [6]

Further, defining an angle α=β−θ and letting β=ωt, with ω an angularrotational frequency of the magnetic field B, then α=β−θ and therefore,d²α/dt²−d²θ/dt². Equation [3] becomes:(mL/4)(d ² θ/dt ²)=2μB/L sin α−C(ω−da/dt)²  [7]

For a constant lead angle α, this simplifies to:sin α=CLω ²/2μB  [8]

A maximum frequency ω_(o) that preserves a constant lead angle α isω_(o) ²=2μB/CL,  [9]

where α=π/2, that is, 90 degrees.

At some angular frequency greater than ω_(o) the moment μ cannot followthe field rotation and the system becomes destabilized. At much higherfrequency, the motion substantially halts, since half of the time thefield leads by less than π/2 and for the other half of the time it leadsby greater than π/2. Thus, the two torques effectively cancel. From thisreasoning, the kinetic energy shows a frequency dependence such as shownin FIG. 21C. Specifically, the kinetic energy T is:T=2×(½)(m/2)(L/2)²(dθ/dt)²  [10]

FIG. 21C is a graph expressing this dependence of kinetic energy of therod on frequency of rotation in which the maximum energyT_(o)=(ml²/8)ω_(o) ² where ω_(o)=dθ/dt. That is, the peak rotationalkinetic energy available for a single rod depends on the rod mass,length, and is quadratic in the angular velocity up to the point wherethe rod cannot follow the field rotation.

With the above understanding of the formation and mechanical behavior ofa rod of magnetic nanoparticles, the use of the system and methods as itapplies to medical applications can be shown. The system ofnanoparticles has been found to behave (and appear visually) as a groupof flexible magnetic rods acting on occlusions in blood vessels. First,the treatment of the two characteristic problematic cases discussed withFIGS. 16A and 16B, above, will be shown with the introduction ofrotating rods.

FIG. 22A illustrates a practical benefit of the introduction ofturbulence with spinning rods. FIG. 22A illustrates a portion of avessel having complete spatial blockage being treated using the methodsdescribed herein, in contrast to the conventional treatment illustratedin FIG. 16A. FIG. 22A is a cross section view of lumen 2000 with noflow, having a clot 2005, with a fresh supply of thrombolytic drug 2010being injected near the occlusion. Three spinning magnetic rods 2030(not to scale) have been shown injected along with the fresh drug 2010,and they generate local turbulence as they are pulled in the direction2025 of a rotating magnet source (not shown here). With a clockwisespinning rotation the rods are shown co-mingling with the fresh drug,and brushing the surface of the clot 2005 as they move slowly to theleft as the external rotating magnetic field source moves. The tinyparticles of clot 2005 accumulate at the right, where they will form aball, when the rotation is continued, as illustrated in FIG. 23A.

In some embodiments, the removal of the clot 2005 occurs withoutmechanical scouring of the clot material. In some embodiments, theprincipal mechanism for removal of the clot 2005 is not the abrasion ofthe magnetic rods 2030 scraping pieces of the clot 2005. In someembodiments, the principal mechanism for removal of the clot 2005 is notdue to hyperthermia caused by inductive heating of the magnetic rods2030 arising from an alternating magnetic field. In some embodiments,the magnetic rods 2030 do not have an abrasive coating. In someembodiments, the magnetic rods 2030 have a non-abrasive coating. Thesituation is to be compared with that of FIG. 16A, in a staticapplication of drug that would have little mixing action, and mustdepend on lengthy time for removal of the clot. In some embodiments, themagnetic nanoparticles can be manipulated to form a vortex, e.g.predictably circulate, in a region of stagnant flow to better mix anadjunct, resulting in a more efficient chemical interaction. Creating avortex can also draw in more of the adjunct near the region of turbulentflow. The circulation can occur at a frequency greater than or equal toabout 0.1 Hz and/or less than or equal to about 5 Hz, or a frequencygreater than or equal to about 0.25 Hz and/or less than or equal toabout 3 Hz, or overlapping ranges thereof.

FIG. 22B is a cross section view of the upper part of a lumen 2050 inwhich example embodiments of methods and devices are shown solving theproblem of inefficient clot removal by standard methods in the case asshown in FIG. 16B. This case might represent partial blockage in a legartery. In some embodiments, there is slowly flowing blood 2090 in thepartially blocked lumen 2050, as was exhibited in FIG. 16B. Clotmaterial 2058 and 2062 has built up around valve leaflet 2060,stiffening it and causing significant but not total flow reduction. Inthis case, the vessel 2050 is not totally closed, and the reduced flowis due to the partial occlusion and rigidity of rigid valve 2060. Asdescribed in relation to FIG. 16B the blood flow, though slow, carriesoff injected drug with inefficient contact with the occluding material.In some embodiments of the method, the actions of rotating scouring rods2055 acting on clots 2058 and 2062 can be shown to greatly increase thedrug contact, as well as provide gentle scuffing on a small scale.Turbulent flow in regions 2080 and 2085 is generated by the rotatingrods 2055 whose relatively small and flexible structure can work in suchregions without substantially or significantly damaging the vessel wall2070 or valve leaf 2060. In some cases the removed magnetically infusedmaterial will be collected downstream by magnetic means.

In some embodiments, a principal mechanism for removal of the clotmaterial 2058 and 2062 is not the abrasion of the rotating rods 2055scraping pieces of the clot material 2058 and 2062. In some embodiments,the principal mechanism for removal of the clot material 2058 and 2062is not due to hyperthermia caused by inductive heating of the rotatingrods 2030 arising from a time-varying magnetic field. In someembodiments, the magnetic rods 2030 do not have an abrasive coating. Insome embodiments, the rotating rods 2030 have a non-abrasive coating.

When the rotation is continued under certain conditions (especially lowflow) the clot material and magnetic nanoparticles can form a magneticball, as described in FIG. 23B below. Again, without being bound by aparticular theory, it is believed that as the magnetic nanoparticlescirculate they may engage the surface of the thrombus. As the thrombusbreaks into tiny pieces, the magnetic nanoparticles become encapsulatedin a ball-like structure that comprises the magnetite and thrombusmaterials. This structure has several advantageous properties, inaccordance with several embodiments of the invention.

1. The object can accelerate the destruction of the thrombus byincreasing the surface area of interaction and by causing more efficientcirculation of the thrombolytic drug.

2. The structure can capture smaller emboli, encasing them in the ballstructure, thereby preventing them from escaping.

3. The structure can continue to break down slowly as that structure islysed by the thrombolytic drug.

4. The structure can be recollected with a magnet-tipped device, therebycapturing the larger emboli and the magnetic nanoparticles.

With an appropriate rate of delivery of a drug, depending on the natureand age of a clot and of magnetic rod interaction, the magnetic rodscouring process can be arranged to mix clot material and rods, asdescribed, to provide small, roughly spherical balls of clot materialcombined with the magnetic rods. Those conditions can be determined bythe rate of application and concentration of the thrombolytic drugsduring the magnetic procedure. Physicians trained in the treatment ofocclusions can use judgment of the rate of delivery of drug in order toform the ball of desired or optimal properties (stiffness and size) forcompletion of the removal.

An example application of this technique is described as follows. FIG.23A is a cross section view of a blood vessel 2120, totally occluded bya clot 2130, with no blood flow. Here magnetic rods 2122 are stirringthe region just proximal to clot 2130 with clockwise rotation of themagnetic field, causing circulation pattern 2135. The mixing region 2125contains a mixture of clot material, thrombolytic drug, and a smallamount of magnetic rod material.

In the cross section view of FIG. 23B, this rotational interaction inblood vessel 2120 has continued and a ball 2140 begins to form ofmaterial stripped from clot 2130 using captured emboli, and a smallamount of magnetic rod material.

In FIG. 23C, the rotating ball 2140 has become enlarged and acceleratesthe therapy. It has opened the blocked channel in vessel 2120, leavingminor remains 2150 of occlusion material. The ball 2140 is stillrotating and held in location by the force from the gradient of therotating magnetic source (e.g., magnet).

FIG. 23D shows the means of capture and removal of completed clot ball2140. At an appropriate time, before restored blood flow has pushed thethrombus ball 2140 downstream, a magnet-tipped probe 2145 is insertedand captures the ball structure 1040 for removal by retracting themagnet-tipped probe 2145.

FIG. 24 is a cross section view of blood vessel 2255 containing valveleaflets 2260, one of which, 2262, has occluding material 2263 that hasstiffened valve 2262 to become non-functional. Blood is flowing slowlyin the direction of arrow 2270. An external magnetic field generator,(such as depicted in FIG. 14 or FIG. 15), has generated a rotating fieldin this region into which rotating nanoparticle rods 2275 are acting onclot deposits 2263 in the manner shown, for example, in FIG. 22B above.The magnetic nanoparticle rods 2275 shown may actually be members of alarge number of such rods in the space adjacent the clot deposits 2263.The rods 2275 are flexible and can be brushed to lengths shorter thanthe approximately one to two millimeters as described above, in order tofunction on the narrow corners of the clot deposits 2263. In laboratorytests, the rods 2275 have functioned to remove material in model spacesthat were approximately 2 centimeters wide and 3 millimeters deep andremoved approximately 100 cubic millimeters of thrombus material.

FIG. 25 is a cross section drawing of a small blood vessel 2300branching off a larger vessel 2305. The small blood vessel 2300 may betortuous as shown, but does not hinder the walking travel such as thatof a magnetic rod 2310 shown approaching clot 2315, which might be aclot in a brain or otherwise. Accordingly, the systems and methodsdescribed herein advantageously facilitate movement of magneticnanoparticles, and treatment of fluid obstructions, within tortuous orcurved vasculature (such as the neurovasculature). Such small clots 2315can be scrubbed as described for other, generally larger vessels such as2255 in FIG. 24 above. The scrubbing can be generated to remove piecesof occluding material with the appropriate field and gradient choices.These removed particles may be up to a few microns in size, and may notcause further downstream damage. In accordance with several embodiments,an advantage of this method of clearing a clot such as clot 2315 is thatthe occlusion might be total and difficult to reach by conventionalexisting methods, but the external rotating field provided by thesystems and methods described herein can walk the rods to the occlusionpoint. The thrombolytic drug may then be introduced, if possible, at thesite of the clot 2315. At that point, the stirring activity of themagnetic rods 2310 can make the drug interact with the clot 2315 muchfaster than a static delivery.

Although magnetic nanoparticles are sufficient to gently clear delicatestructures, it may sometimes be desirable to rapidly remove materialquickly, as is the case for ischemic stroke, in which parts of the brainare starved of blood. The same principles used with magneticnanoparticles may be employed with larger magnetic structures which arespecifically designed to rapidly remove occlusions by mechanicalabrasion while simultaneously increasing the flow of thrombolytic drugsto the blockage. These larger magnetic structures, termed here asthrombectomy devices, may be spheres with an abrasive material bonded onthe surface. They can be sub-millimeter in size up to a millimeter ormore, with the consideration that removal after the particular procedureis desirable. This technique can result in smaller residual emboli thanis typically seen with conventional techniques. A further advantage ofthis method over existing procedures is the controllable magneticcharacter of the removed material. The thrombectomy device, which isdepicted herein as a sphere with a magnetic moment (i.e., a “magneticball”), may be tethered to simplify retrieval of the device. In someembodiments, the thrombectomy device can be recovered in a mannersimilar to that proposed for the magnetic nanoparticles, namely, the useof a magnetically-tipped guide wire. The ball's surface may comprise anyone or a combination of the following:

1. Contrast agent or agents which allow visualization with magneticresonance imaging, X-ray, PET, ultrasound technologies, or other imagingmodalities.

2. Drugs which accelerate destruction of the blockage.

3. Surface geometries designed and/or optimized to accelerate grinding.

4. Abrasive surfaces to accelerate grinding.

FIG. 26A illustrates elements of the basic operation of themagnetically-enabled thrombectomy device which is presented as a sphere2430. The ball 2430 possesses a permanent magnetic moment with South2410 and North 2420 ends. An externally applied magnetic field 2450which advances in the counter-clockwise direction 2440 causes the ballto rotate. If the magnetic gradient is absent, as is the case in FIG.26A, no traction is generated against the surface 2460 and the ball doesnot translate.

FIG. 26B depicts the same case as FIG. 26A except that a magneticgradient 2480 is present in a substantially fixed direction 2480 whichgenerates a force in the direction 2480 acting on the magnetic ball 2430to press it against the vessel wall 2460. As a result, traction iscreated and translational motion occurs in direction 2470 with thecounter clockwise rotation 2440 of the field.

An example application of this technique is described as follows. FIG.27A is a cross section view of a blood vessel 2510, totally occluded,with no blood flow. As shown, a magnetic ball 2530 can stir the regionjust proximal to occlusion 2515 while mechanically grinding theocclusion's surface 2522. Contact against surface 2522 is created by agradient in direction 2520 which results in a translational force indirection 2520. Clockwise motion of magnetic ball 2530 causescirculation pattern 2525 to be formed, which accelerates action of thethrombolytic drug.

In the cross section view of FIG. 27B, the rotational interaction inblood vessel 2510 has continued and ball 2530 has deeper penetrationinto occlusion 2515 in the translation direction 2520.

In FIG. 27C, the rotating magnetically-enabled ball 2530 has opened ablocked channel 2535 in vessel 2510, leaving minor remains of occlusionmaterial. In some embodiments, the principal mechanism for removal ofthe occlusion 2515 is not the abrasion of the magnetic ball 2530 againstthe occlusion 2515, but is the increased exposure of the occlusion to atherapeutic agent (e.g., thrombolytic drug). In some embodiments, theprincipal mechanism for removal of the occlusion 2515 is not due tohyperthermia caused by inductive heating of the magnetic ball 2530arising from a time-varying magnetic field. In some embodiments, themagnetic rods 2530 do not have an abrasive coating.

FIG. 27D shows a means of capture and removal of themagnetically-enabled ball 2530 from the vessel 2510. The external field2520 is no longer rotated or is removed, which causes the ball 2530 tono longer translate to the right. At an appropriate time, beforerestored blood flow has pushed the magnetically-enabled ball 2530downstream, a magnet-tipped probe 2540 is inserted and captures ball2530 for removal by retracting magnet-tipped probe 2540.

Cross sectional view FIG. 28A shows a tethered magnetically-enabled ball2610 in vessel 2605. The tether 2630 allows the ball 2610 to rotate withthe magnetic field, using attachments to be shown in FIG. 28B or 28C. InFIG. 28A, the North 2640 and South 2645 ends of the magnet are depictedat the ends of the black arrow. A free rotation of the magnetic field2640-2645 allows grinding of the thrombus or plaque material 2620 insideof the vessel 2605. The tether 2630 ensures the magnet 2610 can bemanually retrieved without the need of the magnetically-tipped wire 2540that was depicted in FIG. 27D. In accordance with several embodiments,tether 2630 will not wind on the ball 2610 under rotation (for example,when designed according to methods and devices of FIGS. 28B and 28C).

FIG. 28B shows a first embodiment of a tether 2660 which allows rotationaround a rotational axis 2650 of magnetic ball 2610. As shown in FIG.28B, a tether end 2665 is inserted through the rotational axis 2650loosely to ensure free rotation about the rotational axis 2650. North2640 and South 2645 arrow depicts the magnetization direction of ball2610.

FIG. 28C shows a second embodiment of a tether. Tether 2670 allowsrotation around the rotational axis 2650 of the magnetic ball 2610(perpendicular to a loop 2675). As shown in FIG. 28C, the tethercomprises a loop 2675 which loosely surrounds the magnetic ball'srotational axis 2650 to ensure free rotation about the rotational axis2650. The North 2640 and South 2645 ends of arrow 2680 depict themagnetization direction of ball 2610.

The technologies described herein also may be used in removingvulnerable plaque 2715 on a vessel 2705 wall, as depicted, for example,in FIG. 29. In FIG. 29, a cross section view of a blood vessel 2705 isshown with vulnerable plaque 2715 on the top and bottom of the vessel2705. A rotating magnetic ball 2710 is shown grinding the plaque 2715 ina manner similar to that used on the occlusion 2515 depicted in FIG. 27Cand the tethered embodiment in FIG. 28A. This is made possible by usingan externally-generated magnetic gradient 2720 to direct the actionupwards towards the plaque 2715. In some embodiments, therapeutic agents(e.g., thrombolytic drugs) may also be present to substantially dissolvethe removed (e.g., ejected) plaque material.

To image the magnetic nanoparticles and magnetically-enabledthrombectomy device with modern imaging technologies, the particles canpossess a coating which makes them substantially opaque to that imagingtechnology. Example contrast coatings include contrast coatingsdetectable by x-ray, PET, MR and ultrasound imaging technologies. Suchcoatings can advantageously provide the ability to reconstruct a vesselwhich would normally be invisible due to the lack of blood flow in thatregion. Likewise, the ability to control and recollect the magneticnanoparticles can result in less toxic side effects, which may resultfrom use of traditional contrast agents. For example, X-ray contrastagents typically require multiple injections because they are swept awaywith blood flow and are not able to travel in high concentrations downlow-flow vessels.

FIG. 30A is a cross section drawing of a small blood vessel 2820branching off a larger vessel 2810. The small vessel 2820 may betortuous, as shown, but does not hinder the walking travel of magneticrod collection and/or the rolling motion of a magnetically-enabled ball.Both technologies are schematically depicted as starting at the rightside of the small vessel 2825 and approaching a blockage 2815. Atsubsequent points in time, the location of the magnetic ball or magnetrod collection 2825 is identified at the points indicated by 2826, 2827,2828, and 2829. The translation direction of the magnetic rod collectionor magnetically-enabled ball is indicated by the arrow 2830 extendingfrom the body.

FIG. 30B is the same cross section drawing depicted in FIG. 30A. In thisview, the imaged locations of the magnetic rod collection or themagnetically-enabled ball are connected, thereby allowing a computer toreconstruct the path 2835 traveled. This path can be referenced againstpreoperative images to confirm the anatomy and to plan procedures usingnavigation along the path 2835.

Compositions for Use in the System

Various formulations of magnetic nanoparticles, whether formulated incombination with pharmaceutical compositions or not, may be used foradministration to a patient. Those of skill in the art will recognizehow to formulate various therapeutic agents (e.g., pharmaceuticalcompositions, drugs and compounds) for co-administration with themagnetic nanoparticles hereof, or administration separate from thenanoparticles. In some embodiments, various formulations of the magneticnanoparticles thereof may be administered neat (e.g., pure, unmixed, orundiluted). In some embodiments, various formulations and apharmaceutically acceptable carrier can be administered, and may be invarious formulations. For example, a pharmaceutically acceptable carriercan give form or consistency, or act as a diluent. Suitable excipientsinclude but are not limited to stabilizing agents, wetting andemulsifying agents, salts for varying osmolarity, encapsulating agents,buffers, and skin penetration enhancers. Example excipients, as well asformulations for parenteral and non-parenteral drug delivery, are setforth in Remington, The Science and Practice of Pharmacy 20th Ed. MackPublishing (2000) the disclosure of which is hereby expresslyincorporated by reference herein.

The magnetic nanoparticles can be formed having a mono-crystalline corewith diameters greater than or equal to about 20 nm and/or less than orequal to about 200 nm, diameters greater than or equal to about 50 nmand/or less than or equal to about 100 nm, or diameters greater than orequal to about 60 nm and/or less than or equal to about 80 nm,overlapping ranges thereof, diameters less than or equal to 170 nm, ordiameters of any integer between about 20 nm and about 200 nm. Themono-crystalline core can be advantageous because the structure allowsfor stronger magnetic interactions when compared with magnetic particlesof similar sizes having poly-crystalline cores. Such nanoparticleshaving reduced magnetic effects can be advantageous for use in imagingapplications, such as using them as contrast agents in MRI. Themono-crystalline magnetic nanoparticles described herein can alsoinclude a coating of polyethylene glycol (PEG), polyethylene oxide(PEO), polyoxyethylene (POE) or other polymer, which can serve as aplatform for attaching other drugs.

Administration of Magnetic Nanoparticles

In some embodiments, the magnetic nanoparticles are formulated foradministration by injection (e.g., intraperitoneally, intravenously,subcutaneously, intramuscularly, etc.), although other forms ofadministration (e.g., oral, mucosal, etc.) can be also used depending onthe circulatory system blockage to be treated. Accordingly, theformulations can be combined with pharmaceutically acceptable vehiclessuch as saline, Ringer's solution, dextrose solution, and the like. Theparticular dosage regimen, i.e., dose, timing and repetition, willdepend on the particular individual, that individual's medical history,and the circulatory system blockage to be treated. Generally, any of thefollowing doses may be used: a dose of about 1 mg/kg body weight; atleast about 750 μg/kg body weight; at least about 500 μg/kg body weight;at least about 250 μg/kg body weight; at least about 100 μg/kg bodyweight; at least about 50 μg/kg body weight; at least about 10 μg/kgbody weight; at least about 1 μg/kg body weight, or less, isadministered. Empirical considerations, such as the half-life of athrombolytic drug, generally will contribute to determination of thedosage.

In accordance with several embodiments, systems and methods are providedfor delivering non-dispersible or difficult to disperse agents (such asembodiments of the magnetic nanoparticles described herein).Administering magnetic nanoparticles by injection can present challengeswhere a substantially consistent infusion mass is desired as a functionof time. The infusion mechanism can include syringes, drip bags,reservoirs, tubing, drip chambers, other mechanisms, or any combinationof these. Magnetic particles can be dispersed in solutions such as, forexample, saline, Ringer's solution, dextrose solution, and the like.After a certain amount of time has elapsed in such solutions, magneticparticles can settle near the bottom of the solution due primarily togravitational forces on the particles possibly resulting in aninconsistent infusion mass.

For example, in certain applications, the magnetic nanoparticles aresupplied in a single-dose vial containing about 500 mg of magneticnanoparticles dispersed in about 17 mL of phosphate buffered saline(PBS), and are designed to be infused over the course of about an hour.These magnetic nanoparticles can settle out of dispersion in about 5 to10 minutes. Thus, the magnetic nanoparticles would settle faster thanthe time used to administer them, thereby causing the infusion mass tobe inconsistent.

Some embodiments of the magnetic nanoparticles described herein arenon-dispersible or difficult to disperse in a fluid. Some embodiments ofthe magnetic nanoparticles described herein include amagnetically-strong, relatively large, single-crystalline core having adiameter greater than or equal to about 50 nm and/or less than or equalto about 200 nm. The magnetic nanoparticles can also be coated with arelatively thin (e.g., less than or equal to about 5 nm, 10 nm, 20 nm,etc.) coating (e.g., polyethylene glycol coating) to reduce the chargeassociated with the particles. For example, the relatively thin coatingcan possess less than 20% of the volume of the magnetic core. In oneembodiment, a 70 nm diameter magnetite nanoparticle can have a 1 nmcoating such that the coating volume is 9% of the magnetic core. Therelatively thin coating advantageously can facilitate control of themagnetic nanoparticles and structuring of the nanoparticles byagglomeration or grouping into chains or rods. In several embodiments,the shell coating is thin enough such that the ability of the magneticnanoparticles to mutually interact is substantially reduced. In variousembodiments, the shell coating can be less than 50%, less than 45%, lessthan 40%, less than 35%, less than 30%, less than 25%, less than 20%,less than 15%, less than 10%, or less than 5% of the volume of themagnetic core of the nanoparticle. To disperse such nanoparticles in afluid, e.g. saline, the thickness of the nanoparticle coating can besubstantially increased and/or the viscosity of the dispersion mediumcan be increased. In some embodiments, systems and methods are providedfor maintaining a substantially consistent infusion mass withoutaltering the thickness of the nanoparticle coating or the viscosity ofthe dispersion medium.

Magnetic particles can be made more dispersible by coating the particleswith a relatively thick coating. As an example, a relatively thickcoating can be applied to magnetic nanoparticles to ensure thenanoparticles remain in steric repulsion, such as magnetite or hematitenanoparticles coated with Dextran or polyethylene glycol surrounding arelatively small polycrystalline, magnetic core (e.g., the magnetic corehas a diameter less than or equal to about 20 nm). In some embodiments,systems and methods for maintaining a consistent infusion mass caninfuse magnetically strong particles without a relatively thick coating,e.g., magnetic nanoparticles described herein having asingle-crystalline core with a diameter greater than or equal to about20 nm and/or less than or equal to about 200 nm. In some embodiments,the relatively thick coating prevents the magnetic particles fromstructuring effectively because the magnetic cores are mechanicallyprevented from sufficiently nearing one another due to the buffering ofthe coating. Magnetic particles can experience steric repulsion becausethey have a relatively thick coating that buffers the interaction of themagnetic particles such that they remain substantially dispersedthroughout the infusion process. In some applications, magneticparticles are coated with a relatively thick coating to reduce themagnetic susceptibility of the particles, like when the magneticparticles are used as contrast agents for use in magnetic resonanceimaging.

In some embodiments, magnetic particles are coated with biodegradablesubstances, hydrophobic drugs, or other such coatings. Such coatings canbe effective in increasing the dispersion of the particles in asolution. In some embodiments, the magnetic nanoparticles describedherein and the infusion methods and systems described hereinadvantageously allow the magnetic nanoparticles to substantially remainin dispersion throughout an infusion process without experiencing stericrepulsion and/or without requiring a relatively thick coating tofacilitate dispersion.

In some embodiments, a system for delivering agents that are not readilydispersed in a solution to ensure predictable delivery of the agents inthe solution comprises a pump (e.g., syringe pump) that, in use, pushesa solvent through tubing towards a subject. The agent delivery orinfusion system can comprise an inlet tubing coupled to the pump that,in use, transports the solvent from the pump and a reservoir coupled tothe inlet tubing that, in use, holds at least a portion of a solutecomprising the agents that are not readily dispersed in the solution. Insome embodiments, the system comprises an agitating mechanism coupled tothe reservoir that, in use, agitates the solvent and the solute tocreate a dispersed solution and an outlet tubing coupled to thereservoir that, in use, transports the dispersed solution to thesubject. In some embodiments, an infusion and delivery system comprisesa support structure and an IV drip bag coupled to the support structurethat, in use, holds at least a portion of the solution with the agentsthat are not readily dispersed and an outlet tube coupled to the IV dripbag that, in use, transports the dispersed solution to the subject.

In some embodiments, an infusion system for delivering agents that arenot readily dispersed in a solution to ensure predictable delivery ofthe agents in the solution comprises a syringe pump that, in use,controls dispersal of contents of two or more syringes. An outlet tubingsection can be coupled to each of the syringes. In some embodiments, amanifold is coupled to the outlet tubing sections that, in use, joinsthe solution from two or more of the syringes for delivery to a subject.The manifold can comprise a manifold valve that, in use, controls fluidflow along the manifold. A delivery tube can be coupled to the manifoldthat delivers the mixed solution from the manifold to the subject. Thedelivery tube can include an outlet valve that, in use, controls fluidflow from the manifold to the delivery tube. In some embodiments, thesyringe pump transfers a portion of the solution from a first syringe toa second syringe by dispersing the solution from the first syringe andcollecting the solution with the second syringe such that the movementof the solution from the first syringe to the second syringe agitatesthe solution to maintain dispersion. In some embodiments, at least oneof the plurality of syringes contains a saline solution.

In accordance with several embodiments, dispersion of the magneticnanoparticles is at least partially maintained through the use ofmicro-bore tubing. Micro-bore tubing can be provided in the infusionmechanism to keep particles entrained in the infusate during theinfusion process. Typical infusion sets include tubing having an innerdiameter of about 4 mm. By decreasing the diameter of the tubing,infusion velocity is increased for a given infusion rate. This increasein velocity can be sufficient to reduce the amount of particles thatsettle in the tubing of the infusion mechanism such that the infusionmass remains substantially consistent throughout the infusion process.For example, a micro-bore tubing can have an inner diameter of less thanor equal to about 1 mm, less than or equal to about 0.7 mm, less than orequal to about 0.5 mm, and/or less than or equal to about 0.3 mm. Theinner diameter can depend on the desired fluid velocity through thetubing, the diameter of the particles to be infused, the length oftubing desired, or any combination of these. FIG. 31 illustrates anembodiment of an infusion system 3100 having micro-bore tubing 3102 thatis at least partially pre-filled with a particle dose that isadministered (e.g., pushed) to the patient with sterile saline 3104 froma syringe pump 3106.

In some embodiments, the dispersion of the particles is at leastpartially maintained through the application of ultrasonic energy. FIG.32A illustrates an example of such a system 3200. The example system3200 includes a particle volume 3202 partially contained within areservoir 3204, inlet tubing 3206 from a syringe pump, outlet tubing3208 leading to a patient, and an ultrasonic transducer 3210 in contactwith the reservoir 3204. The ultrasonic transducer 3210 can produce atimed (e.g., periodic) ultrasonic pulse to maintain the dispersion inthe reservoir 3204. Infusion of the magnetic nanoparticles can be drivenby a saline infusion via a syringe and syringe pump (not shown). In someembodiments, the ultrasonic transducer 3210 delivers substantiallycontinuous ultrasonic energy to the reservoir 3204. In certainembodiments, the reservoir 3204 includes coiled infusion tubing (notshown) in a medium (e.g., a liquid or gel) configured to transmitultrasonic energy to the tubing. The system 3200 delivering theultrasonic energy can include, for example, ultrasonic transducers,ultrasonic pads, ultrasonic vibrators, ultrasonic stirrers, or anycombination of these. In some embodiments, the outlet tubing 3208, or aportion of the outlet tubing 3208, can be micro-bore tubing configuredto maintain dispersion of the particles upon delivery to the patient. Insome embodiments, as illustrated in FIG. 32B, the reservoir 3204 caninclude a diaphragm 3212 that reduces the internal volume for theparticle dispersion 3202 in response to increasing volume from thesyringe/syringe pump infusion. As a result, the diaphragm 3212 pushesthe particle dispersion 3202 in the reservoir 3204 into the outlettubing 3208 as the saline infusion from the syringe pump enters thereservoir from the inlet tubing 3206.

In some embodiments, the dispersion of the magnetic nanoparticles is atleast partially maintained through the application of magnetic fields.FIG. 33 illustrates an example of a system 3300 having a reservoir 3304with a particle volume 3302, an inlet tube 3306 from a syringe, anoutlet tube 3308 to a patient, and at least one magnet 3310 configuredto produce a time-varying magnetic field. The magnetic nanoparticles canrespond to the time-varying magnetic field by moving within thedispersion 3302 to substantially maintain a consistent infusion mass.The one or more magnets 3310 can be permanent magnets configured torotate to produce a time-varying magnetic field. The one or more magnets3310 can be electromagnets that have varying currents induced throughthem to produce a time-varying magnetic field. The one or more magnets3310 can be any combination of permanent magnets and electromagnets. Insome embodiments, more than one rotating magnet 3310 is spaced aroundthe reservoir 3304, rotating in similar or different planes. Themagnetic field can vary with a frequency greater than or equal to about1 Hz and/or less than or equal to about 100 Hz, greater than or equal toabout 5 Hz and/or less than or equal to about 50 Hz, and/or greater thanor equal to about 10 Hz and/or less than or equal to about 30 Hz,greater than or equal to about 1 Hz and/or less than or equal to about10 Hz, or overlapping ranges thereof, less than 100 Hz, less than 50 Hz,less than 30 Hz, less than 10 Hz. In some embodiments, the outlet tubing3308, or a portion thereof, includes micro-bore tubing as describedherein with reference to FIG. 31. In certain embodiments, the reservoir3304 includes a diaphragm (not shown) that reduces the internal volumefor the particle dispersion 3302 in response to increasing volume fromthe syringe/syringe pump infusion, similar to the ultrasonic system 3200illustrated in FIG. 32B.

In some embodiments, the dispersion of the magnetic nanoparticles is atleast partially maintained through the application of mechanicalagitation. FIG. 34 illustrates an example of a system 3400 having a dripbag 3402, a support structure 3404 for supporting the drip bag 3402, anoutlet tube 3406 to the patient, and a mechanical agitator 3408 coupledto the drip bag 3402 and/or support structure 3404. In some embodiments,the system includes a drip chamber with a conical bottom (not shown)coupled to the drip bag 3402 and the outlet tube 3406 which allows auser to view and/or control flow into the outlet tube 3406. Thedispersion can be maintained by continuous or timed agitation of an IVinfusion drip bag 3402 through repeated squeezing of the drip bag 3402.In certain embodiments, the agitator 3408 comprises a mechanicallyactuated bar that squeezes a portion of the bag 3402 in a timed,continuous, periodic, and/or rhythmic manner. The mechanical agitation3408 can be repeated with a frequency greater than or equal to about 0.1Hz and/or less than or equal to about 5 Hz, or a frequency greater thanor equal to about 0.25 Hz and/or less than or equal to about 3 Hz, oroverlapping ranges thereof. In some embodiments, the agitator 3408 canbe an air bladder, or balloon, coupled to a compressor that pulses airto the bladder, pauses to allow the air from the bladder to bleed intothe drip bag 3402, and then repeats. In some embodiments, the agitator3408 can be a mechanical vortexer configured to mechanically agitate theparticle container. In some embodiments, the dispersion in the drip bag3402 can be maintained through any combination of mechanical agitation,ultrasonic energy, and magnetic energy as described herein. In someembodiments, the outlet tubing 3406, or a portion thereof, includesmicro-bore tubing as described herein with reference to FIG. 31.

In some embodiments, the infusion mass is delivered using multiple boluscartridges at timed intervals (e.g., periodic or randomized). FIG. 35illustrates an example embodiment of such an infusion system 3500. Thesystem 3500 includes an infusion pump 3502, multiple syringes 3504 orother delivery mechanisms, the syringes being coupled to amulti-connector or manifold 3506, the multi-connector or manifold 3506coupled to outlet tubing 3508. The multiple syringes 3504 can bepreloaded with individual doses and at least one syringe with saline3510 can be included to infuse (e.g., push) each dose down the outlettubing 3508 and/or flush the infusion line. In some embodiments,ultrasound and/or magnetic energy 3512 can be applied to the injectionpump 3502 to maintain dispersion in one or more syringes 3504. In someembodiments, the outlet tubing 3508, or a portion thereof, includesmicro-bore tubing such as described herein with reference to FIG. 31.

In some embodiments, the dispersion of the particles is at leastpartially maintained through the use of fluid dynamic mixing. FIG. 36Aillustrates an example of such a fluid dynamic mixing system 3600. Inthis example, the fluid dynamic mixing system 3600 includes continuouslymixing syringes 3602 wherein a first syringe 3602 b includes thedispersion 3604, a second syringe 3602 a is empty, and a third syringe3602 c includes a saline solution 3606. The syringes 3602 are fluidiclycoupled by a manifold 3608. The system 3600 includes a valve 3610controlling flow to an outlet tube 3612. The fluid dynamic mixing system3600 can have one or more saline valves 3614 to control the introductionof saline 3606 into the manifold 3602 and/or outlet tubing 3612. Thefluid dynamic mixing system 3600 can function by having the emptysyringe 3602 a withdraw at substantially the same time and/or rate asthe dispersion syringe 3602 b delivers, thereby transferring thedispersion 3604 from one syringe to the other in a substantiallycontinuous manner, as depicted in FIG. 36B. This substantiallycontinuous motion of the fluid can be sufficient to maintain thedispersion. At defined time intervals, the valve 3610 could open toallow the appropriate volume of solution to be delivered to the subject,after which the valve 3610 can close so that the mixing can continue.The saline syringe 3602 c can be included and used to flush thedispersant 3604 from the tubing 3612 into the subject. For example, in adynamic mixing phase the saline valve 3614 can be closed tosubstantially prevent the saline solution from exiting a saline solutionportion of the manifold 3608, and the valve 3610 can be closed tosubstantially prevent the solution from flowing from the manifold 3608to the outlet tube 3612. As another example, in a solution distributionphase the saline valve 3614 can be closed to substantially prevent thesaline solution from exiting a saline solution portion of the manifold3608, and the valve 3610 can be open to allow the solution to flow fromthe manifold 3608 to the outlet tube 3612. As another example, in aflushing phase the valve 3610 and the saline valve 3614 can be open toallow the saline solution to flow from the manifold to the outlet tube3612. In some embodiments, the outlet tubing 3612, or a portion thereof,includes micro-bore tubing such as described herein with reference toFIG. 31.

Having described the magnetomotive stator system and methods ofcontrolling magnetic nanoparticles and other magnetic rods (e.g.,magnetic tools), several advantages can be observed when compared todevices and pharmaceutical compositions currently on the market. First,the ability to combine the magnetic gradient with the magnetic field inan advantageous way that allows for magnetic rotors to be controlledfrom a distance, as opposed to catheters and cannulae which may causeunintended injury to a patient. Second, the ability to construct acompact mechanism that allows for the magnetic field to be changed intime in a simple and precise way, as well as possibly optimized, so thatcontrol is enabled over the wireless rotors, is a significantenhancement in view of pharmaceutical compositions that are hard toprecisely control in vivo at normal dosages.

In addition, in one embodiment, when the magnetic rotors comprisemagnetic nanoparticles, such as magnetite or another ferromagneticmineral or iron oxide, the rotors can be manipulated in a way thatimproves mixing of a chemical or pharmaceutical agent that is in thevicinity of the magnetic nanoparticles. The use of the magnetic gradientcombined with a time-varying magnetic field allows for flow patterns tobe created which then amplifies the interaction of the chemical orpharmaceutical. This mechanism has been observed in animal models forthe destruction of clots within the endovascular system using tPA as athrombolytic. The pharmaceutical compositions can also be attached tothe magnetic nanoparticles to perform the same function. As a result,less of those agents may be used for patient treatment provided that thenanoparticles are able to be navigated to and interact with the desiredtargets using the magnetic gradient and the time-varying magnetic fieldof the system.

In one embodiment, the magnetomotive system can make use of aneasy-to-understand user-interface which allows the user to control therotation plane of the magnetic field in a way that is not presentlyfound. In some embodiments, the user interface comprises a touchscreendisplay. Furthermore, imaging technologies can be incorporated into orused in combination with the user interface such that an operator canhave real-time feedback of the position of the magnetic nanoparticles,allowing for dynamic control and navigation. This can aid the operatorto take steps to increase the effectiveness of the process, for example,by introducing more nanoparticles or more chemical agents. Images of thepatient and/or regions of interest can be incorporated into a user faceto aid an operator, physician, technician, or the like to plan anavigation route for the magnetic nanoparticles. Planning a navigationroute can comprise identifying a therapeutic target, such as a clot,choosing a practical injection site for the nanoparticles, and planninga route through the patient's vasculature to arrive at the targetedobject. During the actual navigation of the magnetic nanoparticles, theoperator can use the original images used to plan the navigation or theuser interface can receive updated images to show the operator, thusproviding real-time imaging and feedback to the operator. The real-timeuser-interface can be coupled with a single-axis or multi-axis roboticarm to allow the operator to substantially continuously control thedirection of nanoparticle infusion in real-time.

As an example, the real-time user interface can incorporate imageinformation from an imaging system. The imaging system can be a systemincorporating one or more imaging modalities, configured to provideimaging data to the magnetomotive system. The imaging data can bederived from x-ray data, PET data, MR data, CT scan data, ultrasonicimaging data, or other imaging modality data. In some embodiments, themagnetic nanoparticles act as contrast agents in conjunction with animaging modality.

The magnetomotive system, in one embodiment, receives imaging data fromthe imaging system. In some embodiments, the imaging data comprisesinformation derived from an imaging modality that, in use, providesinformation about vasculature of a subject, relative position ofmagnetic nanoparticles, fluid flow, fluid obstructions, or anycombination of these. For example, the imaging system can produce imagedata based on ultrasound-based imaging. The imaging system can transmitsound waves aimed at an area of interest and interpret the echoed wavesto produce an image. The ultrasound-based imaging system can beconfigured to provide imaging data in real-time and can be configured toidentify fluid flow, tissue, liquid, magnetic nanoparticles, and thelike. In some embodiments, ultrasound-based imaging is based on Dopplerimaging which provides information about fluid flow. The ultrasoundimaging system can image using frequencies from 1 and 18 MHz. Theultrasound images generated by the ultrasound-based imaging system aretwo-dimensional, three-dimensional, or four-dimensional images.

The magnetomotive system, in one embodiment, registers a reference frameof the magnetomotive system to a reference frame of the imaging systemsuch that the imaging data from the imaging system is mapped topositions relative to the magnetomotive system. In some embodiments,registering the reference frames includes identifying elements of areceived image and mapping those elements to positions within a subject.In some embodiments, registering the reference frames includes receivinginformation about the image system itself such as a physical orientationof an imaging device relative to a subject, depth of scan or image,field of view, and the like such that the magnetomotive system can mapthe received image relative to a coordinate system of the magneticsystem. For example, an ultrasonic imaging system can send informationto the magnetomotive system about the frequencies transmitted into thetargeted area, the orientation of the imaging system relative to thesubject, the position of the imaging system relative to the patient, orany combination of these. As another example, a CT system can includeinformation about the depth of scan of an image, the field of view, theorientation of the system relative to the patient, and the like.

In one embodiment, the magnetomotive system identifies the magneticnanoparticles within the imaging data received from the imaging systemto track the particles, to navigate the particles, to switch betweencontrol modes (e.g. collection mode, vortexing mode, navigation mode,etc.), to monitor drug diffusion, or any combination of these.Identifying the magnetic nanoparticles can include analyzing the imagingdata for signals associated with magnetic nanoparticles. For example, inultrasonic imaging the magnetic nanoparticles can have a distinctivesignal in an image due to their motion, composition, position, behavior,orientation, or any combination of these. As another example, in PETsystems the magnetic nanoparticles can have a distinctive and/oridentifiable signal in an image based on attached contrast agents, thedensity or composition of the nanoparticles, the position of thenanoparticles, or the like.

The magnetomotive system can determine a position of the magneticnanoparticles relative to the magnetomotive system, based on theregistration of the reference frames. The magnetomotive system can plana navigation path from the identified position of the magneticnanoparticles to a desired location within the subject based on theimaging data from the imaging system. For example, the navigation pathcan include an acceptable path through the vasculature of the subjectfrom the current location of the magnetic nanoparticles to the targetedstructure, such as an occlusion. In some embodiments, planning anavigation path comprises identifying a therapeutic target, such as aclot, choosing a practical injection site for the nanoparticles, andplanning a route through the patient's vasculature to arrive at thetherapeutic target.

The magnetomotive system can manipulate a magnetic field produced by themagnetic system to navigate the magnetic nanoparticles according to thenavigation path. In some embodiments, manipulation of the magnetic fieldcauses the magnetic nanoparticles present within the vasculature toagglomerate into a plurality of magnetic nanoparticle rods and causesthe magnetic nanoparticle rods to travel through fluid within thevasculature by repeatedly walking end over end away from the magneticfield in response to rotation of the magnetic nanoparticle rods and themagnetic gradient and (b) flowing back through the fluid towards themagnetic field in response to the rotation of the magnetic nanoparticlerods and the magnetic gradient. In certain embodiments, the circulatingmotion of the magnetic nanoparticles increases exposure of a targetedstructure (e.g. a fluid obstruction) within a blood vessel of thevasculature to a therapeutic agent (e.g. a thrombolytic drug) present inthe blood vessel and accelerates action of the therapeutic agent (e.g.the thrombolytic drug on the fluid obstruction).

The magnetomotive system can also be used to move nanoparticles withinsmall channels in a manner superior to approaches attempted withnon-varying magnetic fields. The combined use of the magnetic gradientwith a time-varying magnetic field allows for the nanoparticles totravel into small vessels, at which point therapy can be directed.

EXAMPLES

Aspects of the disclosure may be further understood in light of thefollowing examples of illustrative embodiments of methods and systems,which should not be construed as limiting the scope of the disclosure orclaims in any way. Moreover, the methods and procedures described in thefollowing examples, and in the above disclosure, need not be performedin the sequence presented.

Example 1 Administration of Magnetic Nanoparticles to Rabbits

Anesthetized rabbits were used to create an endovascular obstructionmodel by using the jugular veins and generating a clot at this locationusing thrombin, a natural product that produces blood clots. Once astable clot was established, tPA (an enzyme commonly used to dissolveclots in endovascular obstruction patients), and magnetic nanoparticleswere directed to the clot location and the length of time to dissolvethe clot was recorded. See FIG. 38. After varying time points, theanimals were euthanized, the remaining clots were weighed and analyzedand tissues were collected to ensure that there was no damage to thevessel itself.

The endovascular obstruction model allows the determination whether themagnetomotive stator system can re-open a vein or artery faster thanwith tPA alone, and if the dosage of tPA can be reduced without causingdamage to the vein. The data gathered from the present endovascularobstruction studies clearly show that the magnetomotive stator systemsignificantly speeds up the “clot-busting” activity of tPA.

Detailed Protocol

Summary: Deep Vein Thrombosis is a common and potentially deadlycondition, and current treatment options can do more harm than good insome cases. Our aim is to use a non-survival anesthetized rabbit modelof venous thrombosis to determine whether we can substantially increasethe efficiency of current pharmacological treatment by manipulatingcommonly used MRI contrast media magnetically (Magnetic particles inimaging: D. Pouliquen et. al., Iron Oxide Nanoparticles for use as anMRI contrast agent: Pharmacokinetics and metabolism; Magnetic ResonanceImaging Vol. 9, pp. 275-283, 1991, the disclosures of which are herebyexpressly incorporated by reference herein).

Magnetics: The iron nanoparticles described above are currently used inhumans and considered safe.

Introduction: Deep Vein thrombosis (DVT) can be asymptomatic, but inmany cases the affected area is painful, swollen, red and engorged withsuperficial veins. Left untreated, complications can include tissuenecrosis and loss of function in the affected limb. A seriouscomplication is that the clot could dislodge and travel to the lungsresulting in a pulmonary embolism (PE) and death. Current treatment ofDVT includes high doses of lytic enzymes such as streptokinase andtissue plasminogen activator (tPA), sometimes augmented with mechanicalextraction (Angiojet, Trellis Infusion System). The doses of lyticenzymes are such that in many patients (particularly elderly) the riskof hemorrhage is high and poor outcomes common (A review ofantithrombotics: Leadley R J Jr, Chi L, Rebello S S, Gagnon A.JPharmacol Toxicol Methods; Contribution of in vivo models of thrombosisto the discovery and development of novel antithrombotic agents. 2000March

April; 43(2):101-16; A review of potential tPA complications:Hemorrhagic complications associated with the use of intravenous tissueplasminogen activator in treatment of acute myocardial infarction, TheAmerican Journal of Medicine, Volume 85, Issue 3, Pages 353-359 R.Califf, E. Topol, B. George, J. Boswick, C. Abbottsmith, K. Sigmon, R.Candela, R. Masek, D. Kereiakes, W. O'Neill, et al., the disclosures ofwhich are hereby expressly incorporated by reference herein). The aim ofthe present DVT model is to allow determination whether themagnetomotive stator system enhances the activity of tPA at the site ofthe thrombus such that a significantly lower dose of tPA can be used,greatly reducing the risk of hemorrhage. Further, current mechanicalthrombolytics are known to damage endothelium. Following eachexperiment, the vessel segment is evaluated histologically forendothelial integrity.

Procedure: This is a non-survival procedure. New Zealand White rabbits(1.5-2.5 kg) are anesthetized using Ketamine 35 mg/kg, Xylazine 5 mg/kgIM and the ventral neck shaved and prepared for surgery. Mask inductionusing isoflurane gas may be used to deepen the anesthetic plane to allowfor orotracheal intubation. In one embodiment, once intubated, theanimal is moved to the operating room and administered isoflurane gasanesthesia (1-5%, to surgical effect) for the duration of the procedure.Heart rate, respiratory rate, body temperature and end-tidal CO₂ aremonitored while the animal is under anesthesia. In an effort to reducethe number of animals and reduce the variability among studies,bilateral 10-12 cm incisions are made paramedian to the trachea andsharp/blunt dissection is used to isolate the jugular veins. If nosignificant complications arise, the total number of animals is reducedaccordingly.

An ultrasonic flow probe is placed on the distal portion of the isolatedvessel and baseline blood flow data is collected for 30 minutes.Following stabilization of venous flow, silk (or other braided,uncoated) suture (5 or 6-0, taper needle) is passed transversely throughthe center of the vessel lumen at the distal aspect of the area to beoccluded, and secured with a loose knot. The function of this suture isto act as an anchor for the clot and prevent embolism. Then, a ligatureis placed on the proximal and distal portion of the vessel (proximal inrelation to the flow probe) to occlude flow. Ultimately a 2 or 3 cmsegment of the vessel is isolated with ligatures. 100-200 U bovinethrombin is administered intravenously (27-30 g needle) into the spaceapproximately 1 mm proximal the first ligature. The proximal ligature isplaced immediately following withdrawal of the thrombin needle. Theentry site of the needle is closed with a small drop of Vetbond® toprevent bleeding during the lysis procedure. The clot is allowed tomature and stabilize for 30 minutes at which time the ligatures areremoved and tPA or a combination of tPA with magnetic nanoparticles(described above) are injected at the antegrade aspect of the vein(27-30 g needle, entry hole again sealed with Vetbond®). A dynamicmagnetic field is applied to the location and dissolution of the clot ismonitored continuously for up to 3 hours via ultrasonic flowmetry.Following re-establishment of flow the animals are euthanized whilestill under anesthesia with an i.v. overdose of pentobarbital (150 mpk).The experimental vessel segment and residual clot is then collected,weighed and fixed for further analysis. Dosages of tPA used in theendovascular obstruction model range from about 312.5 U to about 5000 U.

Groups: The study is accomplished in 2 phases, Pilot and Proof ofConcept. Both phases include the procedures outlined here, but the PilotPhase utilizes only the left jugular, leaving the other a naïvehistological comparator.

Pilot Groups

1. Thrombin only, no tPA. This group will establish the baseline mass ofour thrombus and allow assessment of thrombus stability.

n=30.

2. tPA only, dose ranging to establish a fully efficacious dose (100%re-cannulation) n=6×3 doses=18

3. tPA only, dose ranging to establish a sub-optimal dose (either 100%effective in 25-50% of subjects, or re-cannulation in all subjects butonly 25-50% of flow rate). tPA is notoriously variable, so thesub-optimal dose may be difficult to find. n=3×4 doses=12

Device alone to establish optimum particle concentration n=3×3concentrations=9.

Proof of Concept Groups:

Note: “n” numbers may be combined with pilot data depending on initialdata quality, further reducing animal requirements.

1. Optimal tPA. n=6

2. Sub-optimal tPA. n=6

3. Device alone. n=6

4. Device+Optimal tPA. n=6

5. Device+sub-optimal tPA. n=6

Two questions can be answered using the present endovascular obstructionmodel:

Small Vessels: Following the completion of the thrombosis procedure inthe jugular veins, the surgical plane of anesthesia is continued and alaparotomy performed. A portion of the bowel is exteriorized and bathedin saline to prevent drying. One of the large veins in the mesentery istied off and cannulated with PE10. A mixture of iron particles andfluoroscene (12.5 mg/ml in 100 ul) is injected and photographed underblack light. This allows the determination whether the fluoroscenediffuses into the very small veins surrounding the bowel, and illustratethat the magnetomotive stator system directs magnetic nanoparticles tothe small vasculature.

Safety: Is damage done to the endothelial lining using the magnetomotivestator system? Does it create hemolysis? The present endovascularobstruction model allows a determination via review of the vena cava.Following the completion of the thrombosis procedure in the jugularveins, the surgical plane of anesthesia is continued and a laparotomyperformed. A 5-6 cm segment of the vena cava is isolated and allbranches tied off. The vessel is tied off and cannulated with PE10.Either iron nanoparticles (12.5 mg/ml in 100 pl) or saline (100 pl) isinjected and the vessel and is magnetically controlled for 3 hours. Atthe end of 3 hours the blood is removed from the vessel segment viavenapuncture and sent for assessment of hemolysis, following euthanasiathe vessel segment is explanted for histological evaluation of theendothelium. Three experiments are performed with particles and threewithout.

Arterial Access

Using the DVT model described above, it has been demonstrated that themagnetomotive stator system significantly enhances tPA efficacy in thisrabbit model. See FIGS. 37A and 37B. Tissues have been gathered thatwere evaluated histologically. There is no damage observed to tissuewhen examined histologically.

Example 2 IV-Administered Nanoparticles can be Collected in an In VivoLigated Rabbit Femoral Artery

New Zealand White rabbits were used as in Example 1, except the femoralartery was used. Through a 3-4 cm incision in the lower abdomen, theleft femoral artery was isolated from the iliac bifurcation to theabdominal wall, and all branches were tied off. Blood flow in the arteryand the abdominal aorta were monitored continuously with a TransonicsDoppler flow probe coupled to a Transonics T206 meter.

In this example, an acute, anesthetized rabbit model of arterialocclusion was used in which the right femoral artery was isolated andligated to simulate an occlusive thrombus and create a static bloodpool. Magnetic nanoparticles (200 mg/kg) were infused intravenously over15 minutes and collected with the magnet system. The presence of asignificant mass of nanoparticles at the ligation was confirmed for eachanimal.

Example 3 The Action of Pulling IV-Administered Nanoparticles Out of theStream can Concentrate a Drug Faster than Diffusion Alone

Evans Blue dye (50 mg) was infused alone over 15 minutes and co-infusedwith magnetic nanoparticles in the presence of the magnet system, usingthe rabbit model of Example 2. The advancement of the dye in theoccluded artery was captured and quantified by image analysis. Theresults demonstrated that diffusion alone quickly diminished, achieving35% penetration of a ligated vessel an hour after administration. Fulldiffusion was accomplished in 25 minutes using magnetic nanoparticles,whereas full diffusion was not possible with the dye alone. The rate ofdiffusion remained strongly linear for the magnetic nanoparticles, witha volume penetration rate of 4% per minute, as shown in the graph inFIG. 38. FIG. 38 illustrates a graph of the exhausted diffusion ofEvan's blue dye alone versus complete diffusion using magneticnanoparticles.

Example 4 Magnetic Mixing of tPA and Magnetic Nanoparticles at a Clot'sSurface Results in Faster Thrombolysis than tPA Alone

This example used an acute anesthetized rabbit model with athrombin-induced occlusive thrombus in the jugular vein. In the example,tPA alone and tPA co-administered with magnetic nanoparticles (1.2 mg)were injected locally and the time to re-canalize the vessel wasmeasured and confirmed by a Doppler flow meter. The tPA dose was takenfrom a published source and ranged from 312 U to 5000 U, with 2500 Ubeing the standard dose. The results demonstrated 3× faster time tore-canalize with the magnet system versus tPA alone, as shown in FIG.39. Similar lysis rates were demonstrated for a 0.25×tPA dose.

Example 5 Faster Thrombolysis Results when Magnetic Nanoparticles areIntravenously Co-Administered with a Thrombolytic Versus theThrombolytic Alone

A common technique for forming clots in arteries was implemented. Theclot was formed near the abdominal wall (approx. 3 cm from the iliacbifurcation) by first, crushing the area to be occluded with guardedhemostats to disrupt the intima (2-3 mm segment of artery) exposingcollagen, tissue factor and other pro-thrombotics from the arterialwall, then applying critical stenosis to the crushed area using 5-0 silksuture tied with a castration knot, such that flow was reduced toapproximately 25% of the baseline flow velocity (approximately 90%reduction in lumen area). Following 3-5 closure/re-open cycles, anocclusive clot formed in 30-60 minutes. The clot was consideredocclusive by the absence of measurable blood flow for 30 minutes.

With the magnet placed above the clot and rotating at 300 rpm, magnetitenanoparticles (600 mg) were co-infused with streptokinase (30,000 U) in20 ml saline over 15 minutes (2000 U/min, 80 ml/hr), followed bystreptokinase alone at 575 U/min (7.3 ml/hr). Control animals receivedthe same streptokinase infusion without the magnet placement or magneticnanoparticles.

The vessel was considered open when flow reached 50% of thepre-occlusion stenosed value (2-2.5 ml/min). In many cases, smallexcursions in flow to 0.3-0.5 were seen during the nanoparticletreatment while the magnet was activated, but not during treatment withstreptokinase alone. The 4 treated arteries opened at 29.5, 13.4, 32 and28 minutes following the beginning of treatment. The controls wereallowed 2 hours and 1 hour respectively with no measurable flowrestoration. Interestingly, after the 1 hour streptokinase controlstudy, nanoparticles and streptokinase were co-administered and themagnet activated, resulting in the vessel opening after 29 min. For theco-administration of streptokinase and nanoparticles, the mean time forclot lysis was 26.4 min with a standard deviation of 7.4 min, and astandard error of 3.3 min. Example data from the Doppler flow-probe isshown in FIG. 40 illustrating magnetic nanoparticle-accelerated clotlysis.

Example 6 Confirmation of In Vivo Clot Lysis Ultrasound Visibility

The ability to visualize the nanoparticles under Doppler ultrasoundimaging offers limited value for stroke therapies. However, fordeep-vein thrombosis applications, such a feature would allow proceduresto be performed in procedure rooms, thus not incurring the costsassociated with an x-ray suite. Because the magnetic nanoparticlescreate flow patterns in the blood, it is possible to visualize bloodflow using Doppler imaging, even if the nanoparticles themselves couldnot be observed. The study demonstrated that complete in vivo clot lysiswas highly visible under Doppler ultrasound imaging.

Using a rabbit, a midline incision (15 cm) of the vena cava was isolatedfrom the right renal vein to the iliac bifurcation and all branchesligated. A PE10 catheter with a flame-flared tip was introduced via theleft femoral vein and advanced past the bifurcation. A ligature (4-0silk) was placed around the vena cava at the bifurcation and thecatheter retracted until the ligature trapped the flared tip. Theproximal aspect of the vena cava was then ligated immediately distalfrom the right renal vein creating an isolated, blood-filled segmentapproximately 8-9 cm long. A thrombus was formed at the proximal end ofthe segment by clamping (atraumatic vascular clamp) 1.5 cm distal theproximal ligation and injecting 50 U of thrombin (30 μl) viavenapuncture (30 g). The needle was slowly withdrawn and the puncturesite sealed with a drop of tissue adhesive. The clot was allowed tomature for 30 minutes prior to clamp removal. 12 mg of nanoparticles and5000 U of tPA were then injected (200 μl) via the femoral catheter andthe magnet started. The thrombolysis was recorded with DopplerUltrasound (Sonosite Turbo M). Complete clot lysis occurred in 11minutes and was highly visible under Doppler ultrasound imaging.

Example 7 In Vitro Studies: Confirmation of 2D Magnetic NanoparticleControl

As an extension to the previous examples, a bifurcated glass phantom wasobtained to investigate the ability to control the direction of thenanoparticles in two dimensions. The parent vessel is 1 mm wide with 0.5mm bifurcations. Control of the nanoparticles is depicted in FIG. 41. In(a)-(b), the nanoparticle collection is split between the bifurcations.In segment (c), the nanoparticles are retracted. In segment (d) thenanoparticles are directed down the lower branch before being againretracted in (e). The nanoparticles are directed along the upward branchin (f).

Investigations were carried out to quantify the relationship between thelytic-agent dose and the lysis rate. Two lytic agents were used in thesestudies: streptokinase and tPA. The clot recipes are summarized below.

Streptokinase Clot Recipe

The clot model used for the streptokinase dissolution test was a bovinefibrinogen/human plasminogen hybrid with clotting initiated with humanthrombin. Bovine fibrinogen from Sigma (F8630) was dissolved into a 197mM Borate buffer solution made with Sigma components (B0252, B9876,S9625). The ratio of this solution was 0.9 grams of fibrinogen to 10 mlof buffer solution. The lyophilized plasminogen and thrombin powderswere dissolved using the buffer solution. The Human plasminogen from EMDChemicals (528175-120 units) was dissolved in 600 μl of buffer to createa 0.2 units/μl solution. The Human thrombin from Sigma (T6884-1K units)was dissolved in 5 ml of buffer to create a 200 units/ml solution.Additionally, a gelatin solution was created using 100 ml of a 100 mMPotassium phosphate solution using Sigma (P5379) and de-ionized water.To this was added 0.5 grams of porcine gelatin (Sigma G2500), 0.1 gramsSodium chloride (Sigma S9625), and 0.01 grams Thimerosal (Sigma T5125).To create the clot samples, 608 μl of fibrinogen solution, 252 μl ofborate buffer, 81 μl of gelatin solution and 10.2 μl of plasminogensolution were combined in a mixing vial and gently swirled for 15seconds. The mixture was then separated into four 230 μl batches towhich 5 μl of thrombin solution was added into each batch. Thecombination was again gently swirled to mix and 100 μl of solution andwas decanted into culture tubes and incubated at 37° C. for 4 minutes topromote clotting. The dissolving solution contained the dosages inphosphate buffered saline that had been augmented with Red #40 dye inborate buffer. (0.02 g Red #40 from CK Products dissolved in 1 ml boratebuffer.) A standard dose of plasminogen was 8 μl of solution, a standarddose of magnetic nanoparticles was 6 μl of Fe₃O₄ (Cathay Pigments 1106),and a standard dose of streptokinase was 12 μl of solution (Sigma 58026of 10 units/μl of phosphate buffered saline). Volumetric balance offractional doses was made up with borate buffer solution.

Example tPA Clot Recipe

The clot model used for the tPA dissolution test was composed of humanfibrinogen and human plasminogen with clotting initiated with bovinethrombin. Human fibrinogen from EMD Chemicals (341576) was dissolvedinto a 197 mM Borate buffer solution made with Sigma components (B0252,B9876, S9625). The ratio of this solution was 1 gram of fibrinogen to11.1 ml of buffer solution. The lyophilized plasminogen and thrombinpowders were dissolved using the buffer solution. Human plasminogen fromEMD Chemicals (528175-120 units) was dissolved in 120 μl of buffer tocreate a 1 unit/μl solution. Bovine thrombin from Sigma (T6200-1K units)was dissolved in 100 μl of buffer to create a 10 units/μl solution. Agelatin solution was created using 100 ml of a 100 mM Potassiumphosphate solution using Sigma (P5379) and de-ionized water. To this wasadded 0.5 grams of porcine gelatin (Sigma G2500), 0.1 grams Sodiumchloride (Sigma S9625), and 0.01 grams Thimerosal (Sigma T5125). Asolution with tantalum nanoparticles was made to add visual contrast tothe clot. This was composed of 0.0231 g of Ta powder (AP Materials010111) in 1 ml of de-ionized water. To create the clot samples, 100 μlof fibrinogen solution, 125 μl of borate buffer, 32 μl of gelatinsolution, 25 μl of tantalum nanoparticles solution and 3 μl ofplasminogen solution were combined in a mixing vial and gently swirledfor 15 seconds. To the mixture, 5 μl of thrombin solution was added andthe combination gently swirled to mix. 100 μl of solution was decantedinto each of two culture tubes and incubated at 37° C. for 4 minutes topromote clotting. The dissolving solution contained the dosages inphosphate buffered saline. A standard dose of plasminogen was 3 μl ofsolution, a standard dose of magnetic nanoparticles was 12 μl of Fe₃O₄(Cathay Pigments 1106), and a standard dose of tPA was 32 μl of solution(EMD Chemicals 612200 of 78.125 units/μl of phosphate buffered saline).Volumetric balance of fractional doses was made up with borate buffersolution.

FIG. 42 depicts the test-tube model used to quantify the lysis rateusing both streptokinase and tPA. In the figure, the MET sample is onthe left with the magnetic nanoparticles indicated in black. The controlsample is on the right with the arrow indicating the meniscus. Bothsamples use a full dose of streptokinase. The test tubes measure about 5mm in width and the ruler is subdivided into 0.5 mm tick marks. Theartificial thrombus was intentionally constructed to be dense in orderto slow down the lysis rate. These relatively slow models made trackingthe fall of the meniscus easier for both the MET and control samples andresulted in better wall adhesion. For streptokinase, typical total METlysis times using streptokinase were under about 7 hrs. For tPA, METlysis rates were under about 4 hrs. Models in which lysis occurred inless than 1 hr resulted in clot fragmentation that made quantificationof the rate of lysis problematic. FIG. 43 depicts the relative doseresponse improvement possible with MET using streptokinase and tPA,respectively. For a relative lytic-agent dose=1, MET results in lysisabout 11.5 times faster for streptokinase and about 3 times faster fortPA (versus the control). Not captured in these plots is the result thatwhen no lytic agent is used with MET, no lysis occurs. This suggeststhat there is a rapid fall-off at relative lytic doses less than about⅛th for streptokinase and about 1/32nd for tPA. The linear fits suggestequivalent lysis rates at about 1/80th dose for streptokinase and about1/60th dose for tPA. The above work was performed using about a 0.01 Tfield at about a 5 Hz frequency, and exploratory work using fields fromabout 0.01-0.03 T and frequencies from about 1-10 Hz have shown littleimpact on these results.

Example 8 Comparing Lysis Rates and Nanoparticle Dose

An in vitro test tube study was performed to measure the effects of amagnetic nanoparticle dose with a common tPA dose. The clot recipedetailed in Example 7 was used in the model. FIG. 44 is a captured imageof the test tube setup. In the figure, the tPA dose is common across allsamples and the multipliers refer to the magnetic nanoparticle dose. Inthis study, the magnetic nanoparticle doses were exponentially reducedfrom the starting (1×) dose of 0.28 mg. Common to all samples is 625 Uof tPA.

Not depicted are the effects of a 1× nanoparticle dose when no tPA ispresent, which resulted in no measurable lysis. This confirms that, inaccordance with several embodiments, the technology described herein ispharmacomechanical in nature, and that the nanoparticles themselves maynot generate measurable forces on the thrombus.

FIG. 45 depicts the change in the relative lysis rate for a change inthe relative nanoparticle dose, where the 1× nanoparticle dose is thereference. Larger doses of nanoparticles can result in modest gains inthe lysis rate (a 0.1× dose can reduce the rate by less than 8% ascompared to the 1× dose). In some embodiments, the effectiveness of thenanoparticle dose is related to the clot's exposed surface area and/or atPA dose. Once the surface is saturated, increasing the nanoparticledose may offer little or no benefit. Once there are sufficientnanoparticles to create a macroscopic flow pattern, then morenanoparticles may not be as effective in building stronger fluidiccurrents.

Other Embodiments

The detailed description set-forth above is provided to aid thoseskilled in the art in practicing the systems and methods describedherein. However, the systems and methods described and claimed hereinare not to be limited in scope by the specific embodiments hereindisclosed because these embodiments are intended as illustration ofaspects of the systems and methods. Any equivalent embodiments areintended to be within the scope of this disclosure. Indeed, variousmodifications in addition to those shown and described herein willbecome apparent to those skilled in the art from the foregoingdescription which do not depart from the spirit or scope of thedisclosure. Such modifications are also intended to fall within thescope of the appended claims.

What is claimed is:
 1. A method of increasing fluid flow withinvasculature of a subject through external magnetomotive manipulation ofmagnetic nanoparticles introduced within the vasculature, the methodcomprising: introducing a therapeutic agent within vasculature of asubject; infusing a plurality of magnetic nanoparticles within thevasculature in a manner such that dispersion of the magneticnanoparticles within a solution is maintained during infusion, causing amagnet external to the vasculature and having a magnetic field and adirected magnetic gradient to be positioned and to rotate in a mannersufficient to i) agglomerate the magnetic nanoparticles into a pluralityof agglomerates within the vasculature and ii) travel within thevasculature toward a therapeutic target in an end over end manner inresponse to the rotating magnetic field and the directed magneticgradient of the magnet; and causing the agglomerates to collectivelygenerate a circulating fluid motion within the vasculature proximal tothe therapeutic target by adjusting at least one parameter selected fromthe group consisting of: a rotational frequency of the rotating magneticfield, a plane of the rotating magnetic field with respect to thetherapeutic target, and a distance of the rotating magnetic field withrespect to the therapeutic target, wherein the circulating fluid motionfacilitates contact of the therapeutic agent with the therapeutic targetby enhancing diffusion of the therapeutic agent to the therapeutictarget and by refreshing contact of the therapeutic target with thetherapeutic agent, thereby providing more effective interaction of thetherapeutic agent with the therapeutic target.
 2. The method of claim 1,wherein the therapeutic agent is a thrombolytic drug.
 3. The method ofclaim 1, wherein the therapeutic target is a clot in a cerebral bloodvessel.
 4. The method of claim 1, wherein the therapeutic target is anembolism.
 5. The method of claim 1, wherein the therapeutic target is afluid blockage in an extremity of the subject.
 6. The method of claim 1,wherein the therapeutic target is a coronary occlusion.
 7. The method ofclaim 1, wherein the therapeutic target is selected from the groupconsisting of: fatty buildup, arterial stenosis, arterial restenosis,vein thrombi, arterial thrombi, and cerebral thrombi.
 8. The method ofclaim 1, wherein the therapeutic agent is attached to the magneticnanoparticles prior to introduction.
 9. The method of claim 1, whereinthe therapeutic agent is introduced within the vasculature separate fromthe magnetic nanoparticles.
 10. The method of claim 1, wherein themagnet is a permanent magnet.
 11. The method of claim 1, furthercomprising causing the motor to position the magnet at an effectivedistance and an effective plane with respect to the therapeutic target,and to rotate the magnet at frequency between 1 Hz and 30 Hz.
 12. Amethod of increasing fluid flow within a blood vessel of a subjectthrough external magnetomotive manipulation of magnetic nanoparticlesintroduced within the subject, the method comprising: introducing athrombolytic agent within vasculature of a subject, the thrombolyticagent configured to facilitate lysis of a fluid obstruction within ablood vessel; administering a plurality of magnetic nanoparticles withinthe vasculature at a controlled infusion rate; causing a magnet externalto the vasculature and having a magnetic field and a directed magneticgradient to be positioned and to rotate in a manner sufficient to i)agglomerate the plurality of magnetic nanoparticles within thevasculature to form a plurality of agglomerates and ii) travel withinthe vasculature toward the fluid obstruction within the blood vessel inan end over end manner in response to the rotating magnetic field andthe directed magnetic gradient of the magnet; and causing theagglomerates to collectively generate a circulating fluid motion withinthe blood vessel proximal to the fluid obstruction by adjusting at leastone parameter selected from the group consisting of: a frequency of therotating magnetic field, a plane of the rotating magnetic field withrespect to the fluid obstruction, and a distance of the rotatingmagnetic field with respect to the fluid obstruction, thereby increasingcontact of the therapeutic agent with the fluid obstruction.
 13. Themethod of claim 12, wherein introducing a thrombolytic agent withinvasculature of a subject is performed separately from administering theplurality of magnetic nanoparticles within the vasculature.
 14. Themethod of claim 12, wherein the magnet is a permanent magnet.
 15. Themethod of claim 12, wherein the thrombolytic agent is tissue plasminogenactivator.
 16. The method of claim 12, wherein the fluid obstruction isselected from the group consisting of: a cerebral thrombus, a clot invasculature of the extremities, a coronary occlusion and an embolism.17. A method of increasing fluid flow within vasculature of a subjectthrough external magnetomotive manipulation of magnetic nanoparticlesintroduced within the vasculature, the method comprising: providing amagnetic control system configured for: causing a magnet external tovasculature of a subject and having a magnetic field and a directedmagnetic gradient to be positioned and to rotate in a manner sufficientto i) agglomerate a plurality of magnetic nanoparticles previouslyintroduced into the vasculature into a plurality of agglomerates and ii)travel within the vasculature toward a therapeutic target in an end overend manner in response to the rotating magnetic field and the directedmagnetic gradient of the magnet; and causing the agglomerates tocollectively generate a circulating fluid motion within the vasculatureproximal to the therapeutic target by adjusting at least one parameterselected from the group consisting of: a rotational frequency of therotating magnetic field, a plane of the rotating magnetic field withrespect to the therapeutic target, and a distance of the rotatingmagnetic field with respect to the therapeutic target, therebyincreasing contact of a therapeutic agent previously introduced withinthe vasculature with the therapeutic target.
 18. The method of claim 17,further comprising infusing the magnetic nanoparticles within thevasculature.
 19. The method of claim 17, further comprising infusing thetherapeutic agent within the vasculature.
 20. The method of claim 17,wherein the magnetic control system comprises a user interface having atouchscreen display.